Amlodipine formulations

ABSTRACT

Provided herein are stable amlodipine oral liquid formulations. Also provided herein are methods of using amlodipine oral liquid formulations for the treatment of certain diseases including hypertension and Coronary Artery Disease (CAD).

CROSS-REFERENCE

This application is a continuation of U.S. patent application Ser. No.15/726,901 filed Oct. 6, 2017 which claims the benefit of ProvisionalU.S. Application Ser. No. 62/405,455 filed Oct. 7, 2016, which is herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Hypertension, or high blood pressure, is a serious health issue in manycountries. According to the National Heart Blood and Lung Institute, itis thought that about 1 in 3 adults in the United States alone havehypertension. Left unchecked, hypertension is considered a substantialrisk factor for cardiovascular and other diseases including coronaryheart disease, myocardial infarction, congestive heart failure, strokeand kidney failure. Hypertension is classified as primary (essential)hypertension or secondary hypertension. Primary hypertension has noknown cause and may be related to a number of environmental, lifestyleand genetic factors such as stress, obesity, smoking, inactivity andsodium intake. Secondary hypertension can be caused by drug or surgicalinterventions or by abnormalities in the renal, cardiovascular orendocrine system.

A number of antihypertensive drugs are available for treatinghypertension. Various therapeutic classes of antihypertensive drugsinclude alpha-adrenergic blockers, beta-adrenergic blockers,calcium-channel blockers, hypotensives, mineralcorticoid antagonists,central alpha-agonists, diuretics and rennin-angiotensin-aldosteroneinhibitors which include angiotensin II receptor antagonists (ARB) andangiotensin-converting enzyme (ACE) inhibitors. Angiotensin-convertingenzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), apeptidyl dipeptidase that catalyzes angiotension I to angiotension II, apotent vasoconstrictor involved in regulating blood pressure.

Amlodipine is a calcium channel blocker. It affects the movement ofcalcium into the cells of the heart and blood vessels. As a result,amlodipine relaxes blood vessels and increases the supply of blood andoxygen to the heart while reducing its workload. The structural formulaof amlodipine is as follows:

Amlodipine is currently administered in the form of oral tablets, (e.g.,Norvasc®) or in the form of a refrigerated liquid formulation. Inaddition to the treatment of hypertension, amlodipine tablets have beenused for coronary artery disease (CAD) such as chronic stable angina,vasospastic angina, or angiographically documented coronary arterydisease in patients without heart failure or an ejection fraction <40%.

SUMMARY OF THE INVENTION

Disclosed herein is an oral liquid formulation, comprising: (i)amlodipine benzoate in an amount corresponding to 1.0 mg/ml amlodipinefreebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml toabout 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicondioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi)about 0.15 mg/ml simethicone; (vii) about 1.0 mg/ml of polysorbate 80;and (viii) water; wherein the formulation is stable between about 5±5°C. and about 25±5° C. for at least 12 months. In some embodiments of anoral liquid formulation, the amlodipine benzoate is formed in situ. Insome embodiments of an oral liquid formulation, the amlodipine benzoateis formed by the reaction of a pharmaceutically acceptable salt ofamlodipine that is more soluble in aqueous media than amlodipinebenzoate with a molar excess of sodium benzoate. In some embodiments ofan oral liquid formulation, the salt of amlodipine that is more solublein aqueous media than amlodipine benzoate is selected from amlodipinebesylate, amlodipine tosylate, amlodipine mesylate, amlodipinesuccinate, amlodipine salicylate, amlodipine maleate, amlodipineacetate, and amlodipine hydrochloride. In some embodiments of an oralliquid formulation, the amlodipine benzoate is formed by the reaction ofamlodipine besylate with a molar excess of sodium benzoate. In someembodiments of an oral liquid formulation, the formulation furthercomprises a flavoring agent. In some embodiments of an oral liquidformulation, the formulation further comprises a sweetener. In someembodiments of an oral liquid formulation, the sweetener is sucralose.In some embodiments of an oral liquid formulation, the formulation is inthe form of a suspension. In some embodiments of an oral liquidformulation, the pH of the formulation is between about 3 and about 8.In some embodiments of an oral liquid formulation, the pH is betweenabout 4 and about 5. In some embodiments of an oral liquid formulation,the pH is between about 5 and about 6. In some embodiments of an oralliquid formulation, the formulation is stable at about 25±5° C. for atleast 12 months. In some embodiments of an oral liquid formulation, theformulation is stable at about 5±5° C. for at least 12 months. In someembodiments of an oral liquid formulation, the formulation is stable atabout 25±5° C. for at least 24 months. In some embodiments of an oralliquid formulation, the formulation is stable at about 5±5° C. for atleast 24 months.

Also disclosed herein is a method of treating hypertension in a subjectcomprising administering to that subject an oral liquid formulation,comprising: (i) amlodipine benzoate in an amount corresponding to 1.0mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii)about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropylmethylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) about 1.0mg/ml of polysorbate 80; and (viii) water; wherein the formulation isstable between about 5±5° C. and about 25±5° C. for at least 12 months.In some embodiments of a method of treating hypertension, the amlodipinebenzoate is formed in situ. In some embodiments of a method of treatinghypertension, the amlodipine benzoate is formed by the reaction of apharmaceutically acceptable salt of amlodipine that is more soluble inaqueous media than amlodipine benzoate with a molar excess of sodiumbenzoate. In some embodiments of a method of treating hypertension, thesalt of amlodipine that is more soluble in aqueous media than amlodipinebenzoate is selected from amlodipine besylate, amlodipine tosylate,amlodipine mesylate, amlodipine succinate, amlodipine salicylate,amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. Insome embodiments of a method of treating hypertension, the amlodipinebenzoate is formed by the reaction of amlodipine besylate with a molarexcess of sodium benzoate. In some embodiments of a method of treatinghypertension, the formulation further comprises a flavoring agent. Insome embodiments of a method of treating hypertension, the formulationfurther comprises a sweetener. In some embodiments of an oral liquidformulation, the sweetener is sucralose. In some embodiments of a methodof treating hypertension, the formulation is in the form of asuspension. In some embodiments of a method of treating hypertension,the pH of the formulation is between about 3 and about 8. In someembodiments of a method of treating hypertension, the pH is betweenabout 4 and about 5. In some embodiments of a method of treatinghypertension, the pH is between about 5 and about 6. In some embodimentsof a method of treating hypertension, the formulation is stable at about25±5° C. for at least 12 months. In some embodiments of a method oftreating hypertension, the formulation is stable at about 5±5° C. for atleast 12 months. In some embodiments of a method of treatinghypertension, the formulation is stable at about 25±5° C. for at least24 months. In some embodiments of a method of treating hypertension, theformulation is stable at about 5±5° C. for at least 24 months. In someembodiments of a method of treating hypertension, the hypertension isprimary (essential) hypertension. In some embodiments of a method oftreating hypertension, the hypertension is secondary hypertension. Insome embodiments of a method of treating hypertension, the subject hasblood pressure values greater than or equal to 140/90 mmm Hg. In someembodiments of a method of treating hypertension, the subject is anadult. In some embodiments of a method of treating hypertension, thesubject is elderly. In some embodiments of a method of treatinghypertension, the subject is a child. In some embodiments of a method oftreating hypertension, the formulation is administered to the subject ina fasted state. In some embodiments of a method of treatinghypertension, the formulation is administered to the subject in a fedstate. In some embodiments of a method of treating hypertension, theformulation is further administered in combination with an agentselected from the group consisting of diuretics, beta blockers, alphablockers, mixed alpha and beta blockers, calcium channel blockers,angiotensin II receptor antagonists, ACE inhibitors, aldosteroneantagonists, and alpha-2 agonists.

Also disclosed herein is a method of treating Coronary Artery Disease(CAD) in a subject comprising administering to that subject an oralliquid formulation, comprising: (i) amlodipine benzoate in an amountcorresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of acitrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodiumbenzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/mlof hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone;(vii) about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein theformulation is stable between about 5±5° C. and about 25±5° C. for atleast 12 months. In some embodiments of a method of treating CoronaryArtery Disease (CAD), the amlodipine benzoate is formed in situ. In someembodiments of a method of treating Coronary Artery Disease (CAD), theamlodipine benzoate is formed by the reaction of a pharmaceuticallyacceptable salt of amlodipine that is more soluble in aqueous media thanamlodipine benzoate with a molar excess of sodium benzoate. In someembodiments of a method of treating Coronary Artery Disease (CAD), thesalt of amlodipine that is more soluble in aqueous media than amlodipinebenzoate is selected from amlodipine besylate, amlodipine tosylate,amlodipine mesylate, amlodipine succinate, amlodipine salicylate,amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. Insome embodiments of a method of treating Coronary Artery Disease (CAD),the amlodipine benzoate is formed by the reaction of amlodipine besylatewith a molar excess of sodium benzoate. In some embodiments of a methodof treating Coronary Artery Disease (CAD), the formulation furthercomprises a flavoring agent. In some embodiments of a method of treatingCoronary Artery Disease (CAD), the formulation further comprises asweetener. In some embodiments of an oral liquid formulation, thesweetener is sucralose. In some embodiments of a method of treatingCoronary Artery Disease (CAD), the formulation is in the form of asuspension. In some embodiments of a method of treating Coronary ArteryDisease (CAD), the pH of the formulation is between about 3 and about 8.In some embodiments of a method of treating Coronary Artery Disease(CAD), the pH is between about 4 and about 5. In some embodiments of amethod of treating Coronary Artery Disease (CAD), the pH is betweenabout 5 and about 6. In some embodiments of a method of treatingCoronary Artery Disease (CAD), the formulation is stable at about 25±5°C. for at least 12 months. In some embodiments of a method of treatingCoronary Artery Disease (CAD), the formulation is stable at about 5±5°C. for at least 12 months. In some embodiments of a method of treatingCoronary Artery Disease (CAD), the formulation is stable at about 25±5°C. for at least 24 months. In some embodiments of a method of treatingCoronary Artery Disease (CAD), the formulation is stable at about 5±5°C. for at least 24 months. In some embodiments of a method of treatingCoronary Artery Disease (CAD), the Coronary Artery Disease (CAD) ischronic stable angina, vasospastic angina, or angiographicallydocumented coronary artery disease. In some embodiments of a method oftreating Coronary Artery Disease (CAD), the angiographically documentedcoronary artery disease is in patients without heart failure or anejection fraction <40%. In some embodiments of a method of treatingCoronary Artery Disease (CAD), the formulation is further administeredin combination with an additional anti-anginal agent.

Disclosed herein is an oral liquid formulation, comprising: (i) apharmaceutically acceptable salt of amlodipine; (ii) a buffer; (iii)water; and (iv) optionally one or more agents selected from the groupconsisting of preservatives, flavoring agents, sweetening agents,surfactants, suspensions aids, and antifoaming agents; wherein theformulation is stable between about 5±5° C. and about 25±5° C. for atleast 12 months. In some embodiments of an oral liquid formulation, thepharmaceutically acceptable salt of amlodipine is amlodipine benzoate oramlodipine naphthalene sulfonate. In some embodiments of an oral liquidformulation, the amlodipine benzoate or amlodipine naphthalene sulfonateare formed in situ. In some embodiments of an oral liquid formulation,the amlodipine benzoate or amlodipine naphthalene sulfonate are formedby the reaction of a pharmaceutically acceptable salt of amlodipine thatis more soluble in aqueous media than amlodipine benzoate or amlodipinenaphthalene sulfonate with a molar excess of a salt forming agent. Insome embodiments of an oral liquid formulation, the pharmaceuticallyacceptable salt of amlodipine that is more soluble in aqueous media thanamlodipine benzoate or amlodipine naphthalene sulfonate is amlodipinebesylate. In some embodiments of an oral liquid formulation, the saltforming agent is sodium benzoate. In some embodiments of an oral liquidformulation, the amount of sodium benzoate as the salt forming agent isabout 1.0 mg/ml to about 10.0 mg/ml. In some embodiments of an oralliquid formulation, the salt forming agent is sodiumnaphthalene-2-sulfonate. In some embodiments of an oral liquidformulation, the amount of sodium naphthalene-2-sulfonate as the saltforming agent is about 0.5 mg/ml to about 2.5 mg/ml. In some embodimentsof an oral liquid formulation, the oral liquid formulation comprises asurfactant. In some embodiments of an oral liquid formulation, thesurfactant is polysorbate 80. In some embodiments of an oral liquidformulation, the amount of the surfactant is about 0.1 mg/ml to about2.5 mg/ml. In some embodiments of an oral liquid formulation, the oralliquid formulation comprises a preservative. In some embodiments of anoral liquid formulation, the preservative is selected from the groupconsisting of sodium benzoate, a paraben or paraben salt, andcombinations thereof. In some embodiments of an oral liquid formulation,the amount of preservative is about 0.1 mg/ml to about 2.0 mg/ml. Insome embodiments of an oral liquid formulation, the buffer comprises acitrate buffer. In some embodiments of an oral liquid formulation, thecitrate buffer concentration is about 3 mM. In some embodiments of anoral liquid formulation, the buffer comprises a phosphate buffer. Insome embodiments of an oral liquid formulation, the phosphate bufferconcentration is about 3 mM. In some embodiments of an oral liquidformulation, the oral liquid formulation comprises a suspension aid. Insome embodiments of an oral liquid formulation, the suspension aidcomprises silicon dioxide, hydroxypropyl methylcellulose,methylcellulose, microcrystalline cellulose, carboxymethylcellulosesodium, polyvinylpyrrolidone, or combinations thereof. In someembodiments of an oral liquid formulation, the suspension aid is silicondioxide. In some embodiments of an oral liquid formulation, the amountof silicon dioxide is about 0.1 mg/ml to about 1.0 mg/ml. In someembodiments of an oral liquid formulation, the suspension aid ishydroxypropyl methylcellulose. In some embodiments of an oral liquidformulation, the amount of hydroxypropyl methylcellulose is about 3mg/ml to about 10 mg/ml. In some embodiments of an oral liquidformulation, the suspension aid is a combination of silicon dioxide andhydroxypropyl methylcellulose. In some embodiments of an oral liquidformulation, the amount of silicon dioxide is about 0.1 mg/ml to about1.0 mg/ml and the amount of hydroxypropyl methylcellulose is about 3mg/ml to about 10 mg/ml. In some embodiments of an oral liquidformulation, the oral liquid formulation comprises an antifoaming agent.In some embodiments of an oral liquid formulation, the antifoaming agentis simethicone. In some embodiments of an oral liquid formulation, theamount of the antifoaming agent is about 0.05 mg/ml to about 1.0 mg/ml.In some embodiments of an oral liquid formulation, the formulationcomprises a flavoring agent. In some embodiments of an oral liquidformulation, the oral liquid formulation comprises a sweetener. In someembodiments of an oral liquid formulation, the sweetener is sucralose.In some embodiments of an oral liquid formulation, the oral liquidformulation further comprises unreacted salt forming agent. In someembodiments of an oral liquid formulation, the oral liquid formulationis in the form of a suspension. In some embodiments of an oral liquidformulation, the pH of the oral liquid formulation is between about 3and about 8. In some embodiments of an oral liquid formulation, the pHis between about 4 and about 5. In some embodiments of an oral liquidformulation, the pH is between about 5 and about 6. In some embodimentsof an oral liquid formulation, the amount of the pharmaceuticallyacceptable salt of amlodipine corresponds to about 0.8 mg/ml to about1.2 mg/ml of amlodipine free base. In some embodiments of an oral liquidformulation, the formulation is stable at about 25±5° C. for at least 12months. In some embodiments of an oral liquid formulation, theformulation is stable at about 5±5° C. for at least 12 months. In someembodiments of an oral liquid formulation, the formulation is stable atabout 25±5° C. for at least 24 months. In some embodiments of an oralliquid formulation, the formulation is stable at about 5±5° C. for atleast 24 months.

Also disclosed herein is an oral liquid formulation, comprising: (i) apharmaceutically acceptable salt of amlodipine in an amountcorresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of acitrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodiumbenzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/mlof hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone;(vii) optionally about 1.0 mg/ml of polysorbate 80; and (viii) water;wherein the formulation is stable between about 5±5° C. and about 25±5°C. for at least 12 months. In some embodiments of an oral liquidformulation, the pharmaceutically acceptable salt of amlodipine isamlodipine benzoate or amlodipine naphthalene sulfonate. In someembodiments of an oral liquid formulation, the amlodipine benzoate oramlodipine naphthalene sulfonate are formed in situ. In some embodimentsof an oral liquid formulation, the amlodipine benzoate or amlodipinenaphthalene sulfonate are formed by the reaction of amlodipine besylatewith a molar excess of a salt forming agent. In some embodiments of anoral liquid formulation, the salt forming agent is sodium benzoate. Insome embodiments of an oral liquid formulation, the amount of sodiumbenzoate as the salt forming agent is about 1.0 mg/ml to about 10.0mg/ml. In some embodiments of an oral liquid formulation, the saltforming agent is sodium naphthalene-2-sulfonate. In some embodiments ofan oral liquid formulation, the amount of sodium naphthalene-2-sulfonateas the salt forming agent is about 0.5 mg/ml to about 2.5 mg/ml. In someembodiments of an oral liquid formulation, the formulation furthercomprises a flavoring agent. In some embodiments of an oral liquidformulation, the formulation further comprises a sweetener. In someembodiments of an oral liquid formulation, the sweetener is sucralose.In some embodiments of an oral liquid formulation, the oral liquidformulation further comprises unreacted salt forming agent. In someembodiments of an oral liquid formulation, the formulation is in theform of a suspension. In some embodiments of an oral liquid formulation,the pH of the formulation is between about 3 and about 8. In someembodiments of an oral liquid formulation, the pH is between about 4 andabout 5. In some embodiments of an oral liquid formulation, the pH isbetween about 5 and about 6. In some embodiments of an oral liquidformulation, the formulation is stable at about 25±5° C. for at least 12months. In some embodiments of an oral liquid formulation, theformulation is stable at about 5±5° C. for at least 12 months. In someembodiments of an oral liquid formulation, the formulation is stable atabout 25±5° C. for at least 24 months. In some embodiments of an oralliquid formulation, the formulation is stable at about 5±5° C. for atleast 24 months.

Also disclosed herein is a process for preparing a stable amlodipineoral liquid formulation, the process comprising mixing a first mixturewith a second mixture; the first mixture comprising: (i) amlodipinebenzoate; (ii) sodium benzoate; (iii) optionally polysorbate 80; and(iv) water; and the second mixture comprising: (i) citric acid; (ii)sodium citrate; (iii) sucralose; (iv) optionally a flavoring agent; (v)hydroxypropyl methylcellulose; (vi) simethicone; (vii) silicon dioxide;and (viii) water. In some embodiments of a process for preparing astable amlodipine oral liquid formulation, the first mixture is obtainedby a process comprising: (i) adding water to a first container which isnot stainless steel; (ii) adding amlodipine besylate to the firstcontainer; (iii) adding sodium benzoate to the first container; (iv)optionally adding polysorbate 80 to the first container; and (v)stirring until amlodipine benzoate substantially precipitates. In someembodiments of a process for preparing a stable amlodipine oral liquidformulation, the second mixture is obtained by a process comprising: (i)adding water to a second container; (ii) adding citric acid to thesecond container; (iii) adding sodium citrate to the second container;(iv) adding sucralose to the second container; (v) optionally adding theflavoring agent to the second container; (vi) adding hydroxypropylmethylcellulose to the second container; (vii) adding simethicone to thesecond container; (viii) adding silicon dioxide to the second container;and (ix) stirring.

Also disclosed herein is a process for preparing a stable amlodipineoral liquid formulation, the process comprising mixing a first mixturewith a second mixture; the first mixture comprising: (i) amlodipinenaphthalene sulfonate; (ii) optionally sodium benzoate; (iii) optionallypolysorbate 80; and (iv) water; and the second mixture comprising: (i)citric acid; (ii) sodium citrate; (iii) sucralose; (iv) optionally aflavoring agent; (v) hydroxypropyl methylcellulose; (vi) simethicone;(vii) silicon dioxide; and (viii) water. In some embodiments of aprocess for preparing a stable amlodipine oral liquid formulation, thefirst mixture is obtained by a process comprising: (i) adding water to afirst container which is not stainless steel; (ii) adding amlodipinebesylate to the first container; (iii) adding sodiumnaphthalene-2-sulfonate to the first container; (iv) adding sodiumbenzoate to the first container; (v) optionally adding polysorbate 80 tothe first container; and (vi) stirring until amlodipine naphthalenesulfonate substantially precipitates. In some embodiments of a processfor preparing a stable amlodipine oral liquid formulation, the secondmixture is obtained by a process comprising: (i) adding water to asecond container; (ii) adding citric acid to the second container; (iii)adding sodium citrate to the second container; (iv) adding sucralose tothe second container; (v) optionally adding the flavoring agent to thesecond container; (vi) adding hydroxypropyl methylcellulose to thesecond container; (vii) adding simethicone to the second container;(viii) adding silicon dioxide to the second container; and (ix)stirring. In some embodiments of a process for preparing a stableamlodipine oral liquid formulation, the first mixture does not comprisesodium benzoate and the second mixture further comprises a paraben.

Also disclosed herein is a method of treating hypertension in a subjectcomprising administering to that subject a therapeutically effectiveamount of an amlodipine oral liquid formulation comprising: (i) apharmaceutically acceptable salt of amlodipine in an amountcorresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of acitrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodiumbenzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/mlof hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone;(vii) optionally about 1.0 mg/ml of polysorbate 80; and (viii) water;wherein the formulation is stable between about 5±5° C. and about 25±5°C. for at least 12 months. In some embodiments of a method of treatinghypertension, the pharmaceutically acceptable salt of amlodipine isamlodipine benzoate or amlodipine naphthalene sulfonate. In someembodiments of a method of treating hypertension, the amlodipinebenzoate or amlodipine naphthalene sulfonate are formed in situ. In someembodiments of a method of treating hypertension, the oral liquidformulation further comprises unreacted salt forming agent. In someembodiments of a method of treating hypertension, the salt forming agentis sodium benzoate. In some embodiments of a method of treatinghypertension, the salt forming agent is sodium naphthalene-2-sulfonate.In some embodiments of a method of treating hypertension, thehypertension is primary (essential) hypertension. In some embodiments ofa method of treating hypertension, the hypertension is secondaryhypertension. In some embodiments of a method of treating hypertension,the subject has blood pressure values greater than or equal to 140/90mmm Hg. In some embodiments of a method of treating hypertension, thesubject is an adult. In some embodiments of a method of treatinghypertension, the subject is elderly. In some embodiments of a method oftreating hypertension, the subject is a child. In some embodiments of amethod of treating hypertension, the formulation is administered to thesubject in a fasted state. In some embodiments of a method of treatinghypertension, the formulation is administered to the subject in a fedstate. In some embodiments of a method of treating hypertension, theformulation is further administered in combination with an agentselected from the group consisting of diuretics, beta blockers, alphablockers, mixed alpha and beta blockers, calcium channel blockers,angiotensin II receptor antagonists, ACE inhibitors, aldosteroneantagonists, and alpha-2 agonists.

Also disclosed herein is a method of treating Coronary Artery Disease(CAD) in a subject comprising administering to that subject atherapeutically effective amount of an amlodipine oral liquidformulation comprising: (i) a pharmaceutically acceptable salt ofamlodipine in an amount corresponding to 1.0 mg/ml amlodipine freebase;(ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v)about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/mlsimethicone; (vii) optionally about 1.0 mg/ml of polysorbate 80; and(viii) water; wherein the formulation is stable between about 5±5° C.and about 25±5° C. for at least 12 months. In some embodiments of amethod of treating Coronary Artery Disease (CAD), the pharmaceuticallyacceptable salt of amlodipine is amlodipine benzoate or amlodipinenaphthalene sulfonate. In some embodiments of a method of treatingCoronary Artery Disease (CAD), the amlodipine benzoate or amlodipinenaphthalene sulfonate are formed in situ. In some embodiments of amethod of treating Coronary Artery Disease (CAD), the oral liquidformulation further comprises unreacted salt forming agent. In someembodiments of a method of treating Coronary Artery Disease (CAD), thesalt forming agent is sodium benzoate. In some embodiments of a methodof treating Coronary Artery Disease (CAD), the salt forming agent issodium naphthalene-2-sulfonate. In some embodiments of a method oftreating Coronary Artery Disease (CAD), the Coronary Artery Disease(CAD) is chronic stable angina, vasospastic angina, or angiographicallydocumented coronary artery disease. In some embodiments of a method oftreating Coronary Artery Disease (CAD), the angiographically documentedcoronary artery disease is in patients without heart failure or anejection fraction <40%. In some embodiments of a method of treatingCoronary Artery Disease (CAD), the formulation is further administeredin combination with an additional anti-anginal agent.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows the amount of amlodipine remaining in solution over time.

FIG. 2 shows the amount of amlodipine in solution for (x) amlodipinebesylate and (o) amlodipine benzoate in the presence of added sodiumbenzoate.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are stable amlodipine oral liquid formulations. Theseamlodipine formulations described herein are useful for the treatment ofhypertension and coronary artery disease. The formulations areadvantageous over conventional solid dosage administration of amlodipineranging from ease of administration, accuracy of dosing, accessibilityto additional patient populations such as to children and the elderly,and an increased patient compliance to medication.

It is generally known that certain segments of the population havedifficulty ingesting and swallowing solid oral dosage forms such astablets and capsules. As many as a quarter of the total population hasthis difficulty. Often, this leads to non-compliance with therecommended medical therapy with the solid dosage forms, therebyresulting in rending the therapy ineffective. Further, solid dosageforms are not recommended for children or elderly due to increased riskin choking.

Furthermore, the dose of amlodipine to be given to children iscalculated according to the child's weight. When the calculated dose issomething other than the amount present in one or more intact soliddosage forms, the solid dosage form must be divided to provide thecorrect dose. This leads to inaccurate dosing when solid dosages forms,such as tablets, are compounded to prepare other formulations forchildren.

For amlodipine, one solution to overcoming the use of the tablet form isfor a compounding pharmacist to pulverize and crush the amlodipinetablet(s) into a powder via mortar and pestle and reconstitute thepowder in some liquid form. However, forming a amlodipine oral liquid inthis fashion has significant drawbacks including large variability inthe actual dosage, incomplete solubilizing of the amlodipine tablet inthe liquid, rapid instability, inconsistent formulation methods percompounding pharmacy, and a number of other potential issues. Thecrushed tablet liquid formulation may also be potentially unsafe due tocontamination with residual drugs and other substances from the mortarand pestle or other crushing agent.

The present embodiments described herein provide a safe and effectiveoral administration of amlodipine for the treatment of hypertension andother disorders. In particular, the embodiments provide stableamlodipine oral liquid formulations.

As used herein, “amlodipine” refers to amlodipine base, its salt, orsolvate or derivative or isomer or polymorph thereof. Suitable compoundsinclude the free base, the organic and inorganic salts, isomers, isomersalts, solvates, polymorphs, complexes etc. U.S. Pat. Nos. 4,572,909,4,879,303, 6,846,931 and WO2002/053134 disclose amlodipine and exemplaryamlodipine salt forms. In some embodiments, the amlodipine used in theformulations described herein is a pharmaceutically acceptableamlodipine salt. In some instances, the amlodipine salt is amlodipinebenzoate. In other instances, the amlodipine salt is in the form ofamlodipine naphthalene sulfonate.

Amlodipine Oral Liquid Formulations

Oral liquids include, but are not limited to, solutions (both aqueousand nonaqueous), suspensions, emulsions, syrups, slurries, juices,elixirs, dispersions, and the like. It is envisioned thatsolution/suspensions are also included where certain componentsdescribed herein are in a solution while other components are in asuspension. In some embodiments, the oral liquid formulation is asuspension.

In one aspect, the amlodipine liquid formulations described hereincomprise a pharmaceutically acceptable salt of amlodipine, a buffer,water, and optionally one or more agents selected from the groupconsisting of preservatives, flavoring agents, sweetening agents,surfactants, suspension aids, and antifoaming agents. In one embodiment,the buffer is a citrate buffer. In one embodiment, the buffer comprisescitric acid. In some embodiments, the buffer further comprises sodiumcitrate. In one embodiment, the buffer is a phosphate buffer. In oneembodiment, the optional sweetening agent is sucralose. In oneembodiment, the optional sweetening agent is a combination of sucraloseand maltodextrin. In one embodiment, the optional sweetening agent isnot maltitol. In another embodiment, the optional sweetening agent isnot sucrose. In another embodiment, the optional preservative is sodiumbenzoate. In some embodiments, the optional preservative is a paraben.In some embodiments, the optional preservative is a mixture of parabens.In one embodiment, the optional surfactant is a polysorbate. In someembodiments, the optional surfactant is polysorbate 80. In oneembodiment, the optional suspension aid is silicon dioxide. In someembodiments, the silicon dioxide is colloidal silicon dioxide. In someembodiments, the optional suspension aid is hydroxypropylmethylcellulose. In some embodiments, the optional suspension aid is acombination of hydroxypropyl methylcellulose and silicon dioxide. Insome embodiments, the optional suspension aid is polyvinylpyrrolidone.In some embodiments, the optional suspension aid is methyl cellulose. Inone embodiment, the optional antifoaming agent is simethicone.

Pharmaceutically Acceptable Salt of Amlodipine in the Oral LiquidFormulations

Disclosed herein is a stable amlodipine oral liquid formulation. In someembodiments, the stable amlodipine oral liquid formulation is in theform of a suspension. In some embodiments, the stable amlodipine oralliquid formulation comprises a pharmaceutically acceptable salt ofamlodipine which is not soluble in an aqueous media.

In some embodiments, the pharmaceutically acceptable salt of amlodipineis amlodipine benzoate or amlodipine naphthalene sulfonate. In someembodiments, amlodipine benzoate or amlodipine naphthalene sulfonate areformed in situ. In some embodiments, amlodipine benzoate or amlodipinenaphthalene sulfonate are formed by the reaction of a pharmaceuticallyacceptable salt of amlodipine that is more soluble in aqueous media thanamlodipine benzoate or amlodipine naphthalene sulfonate with a molarexcess of a salt forming agent. In some embodiments, thepharmaceutically acceptable salt of amlodipine that is more soluble inaqueous media than amlodipine benzoate or amlodipine naphthalenesulfonate is selected from the group consisting of amlodipine besylate,amlodipine tosylate, amlodipine mesylate, amlodipine succinate,amlodipine salicylate, amlodipine maleate, amlodipine acetate, andamlodipine hydrochloride. In some embodiments, the pharmaceuticallyacceptable salt of amlodipine that is more soluble in aqueous media thanamlodipine benzoate or amlodipine naphthalene sulfonate is amlodipinebesylate.

In some embodiments, the pharmaceutically acceptable salt of amlodipineis amlodipine benzoate and is formed in situ by the reaction of apharmaceutically acceptable salt of amlodipine that is more soluble inaqueous media than amlodipine benzoate with a benzoate salt formingagent. In some embodiments, the benzoate salt forming agent is benzoicacid, sodium benzoate, calcium benzoate, or potassium benzoate. In someembodiments, an excess of the benzoate salt forming agent is used toform the benzoate salt in situ. In some embodiments, the benzoate saltforming agent is sodium benzoate. In some embodiments, an excess ofsodium benzoate is used to form the benzoate salt in situ. In someembodiments, the amount of sodium benzoate used as the salt formingagent is about 1.0 mg/ml to about 10.0 mg/ml. In some embodiments, theamount of sodium benzoate used as the salt forming agent is about 1.0mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8mg/ml, about 1.9 mg/ml, about 2.0 mg/ml, about 2.1 mg/ml, about 2.2mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml, about 2.6mg/ml, about 2.7 mg/ml, about 2.8 mg/ml, about 2.9 mg/ml, about 3.0mg/ml, about 3.1 mg/ml, about 3.2 mg/ml, about 3.3 mg/ml, about 3.4mg/ml, about 3.5 mg/ml, about 3.6 mg/ml, about 3.7 mg/ml, about 3.8mg/ml, about 3.9 mg/ml, about 4.0 mg/ml, about 4.1 mg/ml, about 4.2mg/ml, about 4.3 mg/ml, about 4.4 mg/ml, about 4.5 mg/ml, about 4.6mg/ml, about 4.7 mg/ml, about 4.8 mg/ml, about 4.9 mg/ml, about 5.0mg/ml, about 5.1 mg/ml, about 5.2 mg/ml, about 5.3 mg/ml, about 5.4mg/ml, about 5.5 mg/ml, about 5.6 mg/ml, about 5.7 mg/ml, about 5.8mg/ml, about 5.9 mg/ml, about 6.0 mg/ml, about 6.1 mg/ml, about 6.2mg/ml, about 6.3 mg/ml, about 6.4 mg/ml, about 6.5 mg/ml, about 6.6mg/ml, about 6.7 mg/ml, about 6.8 mg/ml, about 6.9 mg/ml, about 7.0mg/ml, about 7.1 mg/ml, about 7.2 mg/ml, about 7.3 mg/ml, about 7.4mg/ml, about 7.5 mg/ml, about 7.6 mg/ml, about 7.7 mg/ml, about 7.8mg/ml, about 7.9 mg/ml, about 8.0 mg/ml, about 8.1 mg/ml, about 8.2mg/ml, about 8.3 mg/ml, about 8.4 mg/ml, about 8.5 mg/ml, about 8.6mg/ml, about 8.7 mg/ml, about 8.8 mg/ml, about 8.9 mg/ml, about 9.0mg/ml, about 9.1 mg/ml, about 9.2 mg/ml, about 9.3 mg/ml, about 9.4mg/ml, about 9.5 mg/ml, about 9.6 mg/ml, about 9.7 mg/ml, about 9.8mg/ml, about 9.9 mg/ml, or about 10.0 mg/ml.

In some embodiments, the pharmaceutically acceptable salt of amlodipineis amlodipine naphthalene sulfonate and is formed in situ by thereaction of a pharmaceutically acceptable salt of amlodipine that ismore soluble in aqueous media than amlodipine naphthalene sulfonate witha naphthalene sulfonate salt forming agent. In some embodiments, thenaphthalene sulfonate salt forming agent is 1-naphthalene sulfonic acid,2-naphthalene sulfonic acid, sodium naphthalene-1-sulfonate, sodiumnaphthalene-2-sulfonate, or potassium naphthalene-2-sulfonate. In someembodiments, an excess of the naphthalene sulfonate salt forming agentis used to form the naphthalene sulfonate salt in situ. In someembodiments, the naphthalene sulfonate salt forming agent is sodiumnaphthalene-2-sulfonate. In some embodiments, an excess of sodiumnaphthalene-2-sulfonate is used to form the naphthalene sulfonate saltin situ. In some embodiments, the amount of sodiumnaphthalene-2-sulfonate used as the salt forming agent is about 0.5mg/ml to about 2.5 mg/ml. In some embodiments, the amount of sodiumnaphthalene-2-sulfonate used as the salt forming agent is about 0.5mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9mg/ml, about 1.0 mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3mg/ml, about 1.4 mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, about 2.0 mg/ml, about 2.1mg/ml, about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, or about 2.5mg/ml.

In some embodiments, the amount of the pharmaceutically acceptable saltof amlodipine in the oral liquid formulation corresponds to about 0.8mg/ml to about 1.2 mg/ml of amlodipine free base. In other embodiments,the amount of the pharmaceutically acceptable salt of amlodipine in theoral liquid formulation correspond to about 0.8 mg/ml, about 0.81 mg/ml,about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml,about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml,about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml,about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml,about 0.98 mg/ml, about 0.99 mg/ml, about 1.0 mg/ml, about 1.01 mg/ml,about 1.02, mg/ml, about 1.03 mg/ml, about 1.04 mg/ml, about 1.05 mg/ml,about 1.06 mg/ml, about 1.07 mg/ml, about 1.08 mg/ml, about 1.09 mg/ml,about 1.1 mg/ml, about 1.11 mg/ml, about 1.12, mg/ml, about 1.13 mg/ml,about 1.14 mg/ml, about 1.15 mg/ml, about 1.16 mg/ml, about 1.17 mg/ml,about 1.18 mg/ml, about 1.19 mg/ml, or about 1.2 mg/ml of amlodipinefree base. In some embodiments, the amount of the pharmaceuticallyacceptable salt of amlodipine in the oral liquid formulation correspondsto about 0.9 mg/ml to about 1.1 mg/ml of amlodipine free base. In someembodiments, the amount of the pharmaceutically acceptable salt ofamlodipine in the oral liquid formulation corresponds to about 1.0 mg/mlof amlodipine free base. In some embodiments, the pharmaceuticallyacceptable salt of amlodipine is amlodipine benzoate. In someembodiments, the amount of amlodipine benzoate in the oral liquidformulation corresponds to about 1.0 mg/ml of amlodipine free base. Insome embodiments, the pharmaceutically acceptable salt of amlodipine isamlodipine naphthalene sulfonate. In some embodiments, the amount ofamlodipine naphthalene sulfonate in the oral liquid formulationcorresponds to about 1.0 mg/ml of amlodipine free base.

In some embodiments, the amount of the pharmaceutically acceptable saltof amlodipine corresponds to about 1% w/w to about 16% w/w of the solidsin the oral liquid formulation. In other embodiments, the amount of thepharmaceutically acceptable salt of amlodipine correspond to about 1%w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w,about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w,about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w,about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w,about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w,about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9%w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8%w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7%w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6%w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5%w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w,about 10% w/w, about 10.1% w/w, about 10.2% w/w, about 10.3% w/w, about10.4% w/w, about 10.5% w/w, about 10.6% w/w, about 10.7% w/w, about10.8% w/w, about 10.9% w/w, about 11% w/w, about 11.1% w/w, about 11.2%w/w, about 11.3% w/w, about 11.4% w/w, about 11.5% w/w, about 11.6% w/w,about 11.7% w/w, about 11.8% w/w, about 11.9% w/w, about 12% w/w, about12.1% w/w, about 12.2% w/w, about 12.3% w/w, about 12.4% w/w, about12.5% w/w, about 12.6% w/w, about 12.7% w/w, about 12.8% w/w, about12.9% w/w, about 13% w/w, about 13.1% w/w, about 13.2% w/w, about 13.3%w/w, about 13.4% w/w, about 13.5% w/w, about 13.6% w/w, about 13.7% w/w,about 13.8% w/w, about 13.9% w/w, about 14% w/w, about 14.1% w/w, about14.2% w/w, about 14.3% w/w, about 14.4% w/w, about 14.5% w/w, about14.6% w/w, about 14.7% w/w, about 14.8% w/w, about 14.9% w/w, about 15%w/w, about 15.1% w/w, about 15.2% w/w, about 15.3% w/w, about 15.4% w/w,about 15.5% w/w, about 15.6% w/w, about 15.7% w/w, about 15.8% w/w,about 15.9% w/w, or about 16% w/w of the solids in the oral liquidformulation.

Sweetener in the Amlodipine Oral Liquid Formulations

Sweeteners or sweetening agents include any compounds that provide asweet taste. This includes natural and synthetic sugars, natural andartificial sweeteners, natural extracts and any material that initiatesa sweet sensation in a subject. In some embodiments, a solid/powdersweetener is used in the oral liquid formulation described herein. Inother embodiments, a liquid sweetening agent is used in the oral liquidformulation described herein.

Sweetening agents illustratively include glucose, fructose, sucrose,xylitol, tagatose, sucralose, maltitol, isomaltulose, Isomalt™(hydrogenated isomaltulose), lactitol, sorbitol, erythritol, trehalose,maltodextrin, polydextrose, and the like. Other sweetening agentsillustratively include glycerin, inulin, maltol, acesulfame and saltsthereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodiumcyclamate, saccharin and salts thereof, e.g., saccharin sodium orsaccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin,and the like. Sweetening agents can be used in the form of crude orrefined products such as hydrogenated starch hydrolysates, maltitolsyrup, high fructose corn syrup, etc., and as branded products, e.g.,Sweet Am™ liquid (propylene glycol, ethyl alcohol, and proprietaryartificial flavor combination, Flavors of North America), Sweet Am™powder (Product Code 918.005—maltodextrin, sorbitol, and fructosecombination and Product Code 918.010—water, propylene glycol, sorbitol,fructose, and proprietary natural and artificial flavor combination,Flavors of North America), ProSweet™ (1-10% proprietary plant/vegetableextract and 90-99% dextrose combination, Virginia Dare), Maltisweet™(maltitol solution, Ingredion), Sorbo™ (sorbitol and sorbitol/xylitolsolution, SPI Polyols), Invertose™ (high fructose corn syrup,Ingredion), Rebalance M60 and X60 (sucralose and maltodextrin, Tate andLyle), and Ora-Sweet® and Ora-Sweet-SF®, sugar containing andsugar-free, respectively flavored syrups (Paddock Laboratories, Inc.).Sweetening agents can be used singly or in combinations of two or more.Suitable concentrations of different sweetening agents can be selectedbased on published information, manufacturers' data sheets and byroutine testing.

In some embodiments, the amlodipine oral liquid formulation describedherein comprises a sweetening agent. In some embodiments, the sweeteningagent is sucralose. In some embodiments, the sweetening agent is acombination of sucralose and maltodextrin. In some embodiments, thesweetener is not maltitol. In some embodiments, the sweetener is notsucrose.

In some embodiments, the sweetening agent is present in about 0.5 mg/mlto about 0.9 mg/ml in the oral liquid formulation. In other embodiments,the sweetening agent is present in about 0.51 mg/ml, about 0.52 mg/ml,about 0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml,about 0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.60 mg/ml,about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml,about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml,about 0.69 mg/ml, about 0.70 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml,about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml,about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.80 mg/ml,about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml,about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml,about 0.89 mg/ml, or about 0.90 mg/ml in the oral liquid formulation. Insome embodiments, the sweetening agent is present in about 0.6 mg/ml toabout 0.8 mg/ml in the oral liquid formulation. In some embodiments, thesweetening agent is sucralose and is present in about 0.7 mg/ml in theoral liquid formulation.

In some embodiments, the sweetening agent is present in about 1% w/w toabout 10% w/w of the solids in the oral liquid formulation. In someembodiments, the sweetening agent is present in about 1% w/w, about 1.1%w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w,about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2%w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w,about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w,about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w,about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w,about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w,about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9%w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8%w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7%w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6%w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10% w/w ofthe solids in the oral liquid formulation.

Preservative in the Amlodipine Oral Liquid Formulations

Preservatives include anti-microbials, anti-oxidants, and agents thatenhance sterility. Exemplary preservatives include ascorbic acid,ascorbyl palmitate, BHA, BHT, citric acid, EDTA and its salts,erythorbic acid, fumaric acid, malic acid, propyl gallate, sodiumascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite,parabens (such as methylparaben, ethylparaben, propylparaben,butylparaben and their salts), benzoic acid, sodium benzoate, potassiumsorbate, vanillin, and the like.

In some embodiments, the amlodipine oral liquid formulation describedherein comprises a preservative.

In some embodiments, the preservative is a paraben, or a mixture ofparabens and the sweetener is a sugar (such as, but not limited toglucose, fructose, sucrose, lactose, maltose) or a sugar alcohol (suchas, but not limited to xylitol, mannitol, lactitol, maltitol, sorbitol).In some embodiments, the preservative is a paraben, or a mixture ofparabens and the sweetener is not a sugar or a sugar alcohol.

In some embodiments, the preservative is present in an amount sufficientto provide antimicrobial effectiveness to the amlodipine oral liquidformulation described herein. In some embodiments, the amount ofpreservative sufficient to provide antimicrobial effectiveness isbetween about 0.1 mg/ml and about 2.0 mg/ml. In other embodiments, theamount of preservative sufficient to provide antimicrobial effectivenessis about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13mg/ml, about 0.14 mg/ml, about 0.15 mg/ml, about 0.16 mg/ml, about 0.17mg/ml, about 0.18 mg/ml, about 0.19 mg/ml, about 0.2 mg/ml, about 0.21mg/ml, about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25mg/ml, about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29mg/ml, about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33mg/ml, about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37mg/ml, about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41mg/ml, about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45mg/ml, about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49mg/ml, about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69mg/ml, about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, about 1.0 mg/ml, about 1.1mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, about 1.5mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9mg/ml, or about 2.0 mg/ml. In some embodiments, the preservative issodium benzoate and the amount of sodium benzoate sufficient to provideantimicrobial effectiveness is between about 0.2 mg/ml and about 1.0mg/ml. In some embodiments, the preservative is methyl paraben and theamount of methyl paraben sufficient to provide antimicrobialeffectiveness is between about 1.0 mg/ml and about 2.0 mg/ml. In someembodiments, the preservative is propyl paraben and the amount of propylparaben sufficient to provide antimicrobial effectiveness is betweenabout 0.1 mg/ml and about 0.2 mg/ml.

In some embodiments, the preservative is present in about 0.5% w/w toabout 15% w/w of the solids in the oral liquid formulation. In otherembodiments, the preservative is present in about 0.5% w/w, about 1%w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w,about 6% w/w, about 6.5% w/w, about 7% w/w, about 7.5% w/w, about 8%w/w, about 8.5% w/w, about 9% w/w, about 9.5% w/w, about 10% w/w, about11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w,about 13.5% w/w, about 14% w/w, about 14.5% w/w, or about 15% w/w of thesolids in the oral liquid formulation.

Sweetener and Preservative Incompatibility

Paraben preservatives (especially methylparaben) can react with selectedsugars (glucose, fructose, sucrose, lactose, maltose) and sugar alcohols(xylitol, mannitol, lactitol, maltitol, sorbitol) to formtransesterification reaction products. This can be undesirable from aformulation and stability standpoint as the transesterification createsadditional degradants.

In some embodiments, the amlodipine oral liquid formulation describedherein does not comprise a paraben preservative. In further embodiments,the amlodipine oral liquid formulation described herein does notcomprise a paraben preservative when the formulation also comprises asugar or sugar alcohol.

Buffers in the Amlodipine Oral Liquid Formulations

Buffering agents maintain the pH of the liquid amlodipine formulation.Non-limiting examples of buffering agents include, but are not limitedto sodium bicarbonate, potassium bicarbonate, magnesium hydroxide,magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminumhydroxide/sodium bicarbonate co-precipitate, mixture of an amino acidand a buffer, a mixture of aluminum glycinate and a buffer, a mixture ofan acid salt of an amino acid and a buffer, and a mixture of an alkalisalt of an amino acid and a buffer. Additional buffering agents includecitric acid, sodium citrate, sodium tartrate, sodium acetate, sodiumcarbonate, phosphoric acid, sodium polyphosphate, potassiumpolyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodiumhydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate,tripotassium phosphate, sodium acetate, potassium metaphosphate,magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesiumsilicate, calcium acetate, calcium glycerophosphate, calcium chloride,calcium hydroxide, calcium lactate, calcium carbonate, calciumbicarbonate, and other calcium salts.

In some embodiments, the oral liquid formulation comprises a buffer. Insome embodiments, the oral liquid formulation comprises a citratebuffer. In some embodiments, the buffer in the amlodipine oral liquidformulation described herein comprises citric acid. In some embodiments,the buffer in the amlodipine oral liquid formulation described hereincomprises citric acid and sodium citrate. In some embodiments, thesodium citrate is monosodium citrate. In some embodiments, the sodiumcitrate is disodium citrate. In some embodiments, the sodium citrate istrisodium citrate. In some embodiments, the oral liquid formulationcomprises a phosphate buffer. In some embodiments, the buffer in theamlodipine oral liquid formulation described herein comprises phosphoricacid. In some embodiments, the buffer in the amlodipine oral liquidformulation described herein comprises phosphoric acid and sodiumphosphate. In some embodiments, the buffer in the amlodipine oral liquidformulation described herein comprises sodium phosphate. In someembodiments, the sodium phosphate is sodium dihydrogen phosphate. Insome embodiments, the sodium phosphate is sodium hydrogenphosphate. Insome embodiments, the sodium phosphate is trisodium phosphate.

In some embodiments, the pH of the amlodipine oral liquid formulationdescribed herein is between about 3 and about 8. In some embodiments,the pH of the amlodipine oral liquid formulation described herein isbetween about 4 and about 5. In some embodiments, the pH of theamlodipine oral liquid formulation described herein is between about 5and about 6. In some embodiments, the pH of the amlodipine oral liquidformulation described herein is less than about 4, less than about 4.5,less than about 5, less than about 5.5, less than about 6, less thanabout 6.5, less than about 7, less than about 7.5, or less than about 8.In some embodiments, the pH of the amlodipine oral liquid formulationdescribed herein is about 3, about 3.1, about 3.2, about 3.3, about 3.4,about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7,about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6,about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.2, about 7.3,about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, orabout 8.

In some embodiments, the buffer concentration is between about 1 mM andabout 60 mM. In some embodiments, the buffer concentration is about 1mM, about 1.5 mM, about 2 mM, about 2.5 mM, about 3 mM, about 3.5 mM,about 4 mM, about 4.5 mM, about 5 mM, about 5.5 mM, about 6 mM, about6.5 mM, about 7 mM, about 7.5 mM, about 8 mM, about 8.5 mM, about 9 mM,about 9.5 mM, about 10 mM, about 10.5 mM, about 11 mM, about 11.5 mM,about 12 mM, about 12.5 mM, about 13 mM, about 13.5 mM, about 14 mM,about 14.5 mM, about 15 mM, about 15.5 mM, about 16 mM, about 16.5 mM,about 17 mM, about 17.5 mM, about 18 mM, about 18.5 mM, about 19 mM,about 19.5 mM, about 20 mM, about 20.5 mM, about 21 mM, about 21.5 mM,about 22 mM, about 22.5 mM, about 23 mM, about 23.5 mM, about 24 mM,about 24.5 mM, about 25 mM, about 25.5 mM, about 26 mM, about 26.5 mM,about 27 mM, about 27.5 mM, about 28 mM, about 28.5 mM, about 29 mM,about 29.5 mM, about 30 mM, about 30.5 mM, about 31 mM, about 31.5 mM,about 32 mM, about 32.5 mM, about 33 mM, about 33.5 mM, about 34 mM,about 34.5 mM, about 35 mM, about 35.5 mM, about 36 mM, about 36.5 mM,about 37 mM, about 37.5 mM, about 38 mM, about 38.5 mM, about 39 mM,about 39.5 mM, about 40 mM, about 40.5 mM, about 41 mM, about 41.5 mM,about 42 mM, about 42.5 mM, about 43 mM, about 43.5 mM, about 44 mM,about 44.5 mM, about 45 mM, about 45.5 mM, about 46 mM, about 46.5 mM,about 47 mM, about 47.5 mM, about 48 mM, about 48.5 mM, about 49 mM,about 49.5 mM, about 50 mM, about 50.5 mM, about 51 mM, about 51.5 mM,about 52 mM, about 52.5 mM, about 53 mM, about 53.5 mM, about 54 mM,about 54.5 mM, about 55 mM, about 55.5 mM, about 56 mM, about 56.5 mM,about 57 mM, about 57.5 mM, about 58 mM, about 58.5 mM, about 59 mM,about 59.5 mM, or about 60 mM. In some embodiments, the bufferconcentration is between about 1 mM and about 5 mM, or about 2 mM andabout 4 mM. In some embodiments, the buffer concentration is about 3 mM.

In some embodiments, the buffer in the amlodipine oral liquidformulation described herein comprises citric acid. In some embodiments,citric acid is present in about 0.1 mg/ml to about 1.0 mg/ml in the oralliquid formulation. In other embodiments, citric acid is present inabout 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml,about 0.14 mg/ml, about 0.15 mg/ml, about 0.16 mg/ml, about 0.17 mg/ml,about 0.18 mg/ml, about 0.19 mg/ml, about 0.2 mg/ml, about 0.21 mg/ml,about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml,about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml,about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml,about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml,about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml,about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml,about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml,about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml,about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml,about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml,about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml,about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml,about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml,about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml,about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml,about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml,about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml,about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml,about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml,about 0.98 mg/ml, about 0.99 mg/ml, or about 1.0 mg/ml in the oralliquid formulation. In one embodiment, citric acid is present in about0.31 mg/ml in the oral liquid formulation. In some embodiments, citricacid is present in about 5.0 mg/ml to about 15 mg/ml in the oral liquidformulation. In other embodiments, citric acid is present in about 5.0mg/ml, about 5.5 mg/ml, about 6.0 mg/ml, about 6.5 mg/ml, about 7.0mg/ml, about 7.5 mg/ml, about 8.0 mg/ml, about 8.5 mg/ml, about 9.0mg/ml, about 9.5 mg/ml, about 10.0 mg/ml, about 10.5 mg/ml, about 11.0mg/ml, about 11.5 mg/ml, about 12.0 mg/ml, about 12.5 mg/ml, about 13.0mg/ml, about 13.5 mg/ml, about 14.0 mg/ml, about 14.5 mg/ml, or about15.0 mg/ml in the oral liquid formulation.

In some embodiments, citric acid is present in about 1% w/w to about 45%w/w of the solids in the oral liquid formulation. In other embodiments,citric acid is present in about 1% w/w, about 1.1% w/w, about 1.2% w/w,about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w,about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w,about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9%w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8%w/w, about 4.9% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8%w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w,about 18% w/w, about 19% w/w, about 20% w/w, about 21% w/w, about 22%w/w, about 23% w/w, about 24% w/w, about 25% w/w, about 26% w/w, about27% w/w, about 28% w/w, about 29% w/w, about 30% w/w, about 31% w/w,about 32% w/w, about 33% w/w, about 34% w/w, about 35% w/w, about 36%w/w, about 37% w/w, about 38% w/w, about 39% w/w, about 40% w/w, about41% w/w, about 42% w/w, about 43% w/w, about 44% w/w, or about 45% w/wof the solids in the oral liquid formulation. In some embodiments,citric acid is present in about 1% w/w to about 20% w/w of the solids inthe oral liquid formulation. In some embodiments, citric acid is presentin about 1% w/w to about 1.5% w/w of the solids in the oral liquidformulation.

In some embodiments, the amlodipine oral liquid formulation furthercomprises sodium citrate. In some embodiments, sodium citrate is presentin about 0.1 mg/ml to about 1.0 mg/ml in the oral liquid formulation. Inother embodiments, sodium citrate is present in the oral liquidformulation is about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml,about 0.13 mg/ml, about 0.14 mg/ml, about 0.15 mg/ml, about 0.16 mg/ml,about 0.17 mg/ml, about 0.18 mg/ml, about 0.19 mg/ml, about 0.2 mg/ml,about 0.21 mg/ml, about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml,about 0.25 mg/ml, about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml,about 0.29 mg/ml, about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml,about 0.33 mg/ml, about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml,about 0.37 mg/ml, about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml,about 0.41 mg/ml, about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml,about 0.45 mg/ml, about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml,about 0.49 mg/ml, about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml,about 0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml,about 0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml,about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml,about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml,about 0.69 mg/ml, about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml,about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml,about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml,about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml,about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml,about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml,about 0.93 mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml,about 0.97 mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, or about 1.0 mg/mlin the oral liquid formulation. In one embodiment, sodium citrate ispresent in about 0.36 mg/ml in the oral liquid formulation.

In some embodiments, sodium citrate is present in about 1% w/w to about20% w/w of the solids in the oral liquid formulation. In otherembodiments, sodium citrate is present in about 1% w/w, about 1.1% w/w,about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w,about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9%w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8%w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7%w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 6% w/w, about7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w,about 17% w/w, about 18% w/w, about 19% w/w, or about 20% w/w of thesolids in the oral liquid formulation. In some embodiments, sodiumcitrate is present in about 1% w/w to about 2% w/w of the solids in theoral liquid formulation.

In other embodiments, sodium citrate is not added to the formulation.

In some embodiments, the buffer in the amlodipine oral liquidformulation described herein comprises phosphoric acid. In someembodiments, phosphoric acid is present in about 0.1 mg/ml to about 2.0mg/ml in the oral liquid formulation. In other embodiments, phosphoricacid is present in about 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml,about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, 0.4 mg/ml, about0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, about 1.0 mg/ml, about1.1 mg/ml, about 1.15 mg/ml, about 1.2 mg/ml, about 1.25 mg/ml, about1.3 mg/ml, about 1.35 mg/ml, about 1.4 mg/ml, about 1.45 mg/ml, about1.5 mg/ml, about 1.55 mg/ml, about 1.6 mg/mL, about 1.65 mg/mL, about1.7 mg/ml, about 1.75 mg/ml, about 1.8 mg/ml, about 1.85 mg/ml, about1.9 mg/ml, about 1.95 mg/ml, or about 2.0 mg/ml in the oral liquidformulation.

In some embodiments, phosphoric acid is present in about 1% w/w to about10% w/w of the solids in the oral liquid formulation. In otherembodiments, citric acid is present in about 1% w/w, about 1.1% w/w,about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w,about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9%w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8%w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7%w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6%w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5%w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w,about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4%w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w,about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3%w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w,about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2%w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w,about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10% w/w of thesolids in the oral liquid formulation.

In some embodiments, the buffer in the amlodipine oral liquidformulation described herein comprises sodium hydrogenphosphate. In someembodiments, sodium hydrogenphosphate is present in about 0.1 mg/ml toabout 1.0 mg/ml in the oral liquid formulation. In other embodiments,sodium hydrogenphosphate is present in the oral liquid formulation isabout 0.1 mg/mL, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml,about 0.14 mg/ml, about 0.15 mg/ml, about 0.16 mg/ml, about 0.17 mg/ml,about 0.18 mg/ml, about 0.19 mg/ml, about 0.2 mg/ml, about 0.21 mg/ml,about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml,about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml,about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml,about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml,about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml,about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml,about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml,about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml,about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml,about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml,about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml,about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml,about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml,about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml,about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml,about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml,about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml,about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml,about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml,about 0.98 mg/ml, about 0.99 mg/ml, or about 1.0 mg/ml in the oralliquid formulation.

In some embodiments, sodium hydrogenphosphate is present in about 0.5%w/w to about 5% w/w of the solids in the oral liquid formulation. Inother embodiments, sodium hydrogenphosphate is present in about 0.5%w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w,about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4%w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w,about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3%w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w,about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2%w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w,about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1%w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w,about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about5% w/w of the solids in the oral liquid formulation.

Suspension Aid in the Amlodipine Oral Liquid Formulations

A suspension aid or dispersion aid is used to prevent the settling ofthe pharmaceutically acceptable salt of amlodipine in the oral liquidformulation.

Suitable suspension aids include but not limited to polymers such as3-butoxy-2-hydroxypropylhydroxyethylcellulose, acrylamide homo- andcopolymers, acrylic acid homo- and copolymer, alginates,carboxymethylcellulose (sodium and other salts),carboxymethylhydroxyethylcellulose, carboxy-vinyl copolymers, cellulose,such as microcrystalline cellulose, combinations of microcrystallinecellulose with carboxymethylcellulose sodium (such as Avicel® RC-501,RC-581, RC-591, and CL-611), hydrophobically modified hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropyl guar, hydroxypropylmethylcellulose (such as Benecel K750® or Benecel K1500®),hydroxypropylcellulose, methyl cellulose, natural gums and theirderivatives, xanthan gum, guar gum, gum Arabic, partially and fullyhydrolyzed polyvinyl alcohols, partially neutralized polyacrylic acid,polyalkylene glycol, polysaccharide gums, polyvinylpyrrolidone andderivatives thereof, starch and its derivatives, vinylpyrrolidone homo-and copolymers, water-soluble cellulose ethers, and the mixturesthereof. Other suitable suspension aids include silicon dioxide, silicapowder prepared by precipitating water glass (sodium silicate) withsulfuric acid, which is then dried and sold as a fine powder, fumedalumina (made of primary particles which sinter together to formaggregates), clays such as bentonite, laponites, kaolinite, dickite, andnacrite, pyrophylite, talc, vermiculite, sauconite, saponte, nontronite,and montmorillonite, and organically modified montmorillonite clays. Insome embodiments, the suspension aid comprises silicon dioxide. In someembodiment, the silicon dioxide is colloidal silicon dioxide.

In some embodiments, the amlodipine oral liquid formulation describedherein comprises a suspension aid. In some embodiments, the suspensionaid comprises silicon dioxide, hydroxypropyl methylcellulose,methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, orcombinations thereof. In some embodiments, the suspension aid is silicondioxide. In some embodiments, the suspension aid is hydroxypropylmethylcellulose. In some embodiments, the suspension aid is acombination of silicon dioxide and hydroxypropyl methylcellulose. Insome embodiments, the suspension aid is polyvinylpyrrolidone.

In some embodiments, the suspension aid is present in about 0.1 mg/ml toabout 1.0 mg/ml in the oral liquid formulation. In other embodiments,the suspension aid is present in about 0.1 mg/ml, about 0.15 mg/ml,about 0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml,about 0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml,about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml,about 0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, orabout 1.0 mg/ml in the oral liquid formulation. In some embodiments, thesuspension aid is present in about 0.3 mg/ml to about 0.7 mg/ml in theoral liquid formulation. In some embodiments, the suspension aid ispresent in about 0.4 mg/ml to about 0.6 mg/ml in the oral liquidformulation. In some embodiments, the suspension aid is silicon dioxideand is present in about 0.5 mg/ml in the oral liquid formulation.

In some embodiments, the suspension aid is present in about 3.0 mg/ml toabout 10.0 mg/ml in the oral liquid formulation. In other embodiments,the suspension aid is present in about 3.0 mg/ml, about 3.1 mg/ml, about3.2 mg/ml, about 3.3 mg/ml, about 3.4 mg/ml, about 3.5 mg/ml, about 3.6mg/ml, about 3.7 mg/ml, about 3.8 mg/ml, about 3.9 mg/ml, about 4.0mg/ml, about 4.1 mg/ml, about 4.2 mg/ml, about 4.3 mg/ml, about 4.4mg/ml, about 4.5 mg/ml, about 4.6 mg/ml, about 4.7 mg/ml, about 4.8mg/ml, about 4.9 mg/ml, about 5.0 mg/ml, about 5.1 mg/ml, about 5.2mg/ml, about 5.3 mg/ml, about 5.4 mg/ml, about 5.5 mg/ml, about 5.6mg/ml, about 5.7 mg/ml, about 5.8 mg/ml, about 5.9 mg/ml, about 6.0mg/ml, about 6.1 mg/ml, about 6.2 mg/ml, about 6.3 mg/ml, about 6.4mg/ml, about 6.5 mg/ml, about 6.6 mg/ml, about 6.7 mg/ml, about 6.8mg/ml, about 6.9 mg/ml, about 7.0 mg/ml, about 7.1 mg/ml, about 7.2mg/ml, about 7.3 mg/ml, about 7.4 mg/ml, about 7.5 mg/ml, about 7.6mg/ml, about 7.7 mg/ml, about 7.8 mg/ml, about 7.9 mg/ml, about 8.0mg/ml, about 8.1 mg/ml, about 8.2 mg/ml, about 8.3 mg/ml, about 8.4mg/ml, about 8.5 mg/ml, about 8.6 mg/ml, about 8.7 mg/ml, about 8.8mg/ml, about 8.9 mg/ml, about 9.0 mg/ml, about 9.1 mg/ml, about 9.2mg/ml, about 9.3 mg/ml, about 9.4 mg/ml, about 9.5 mg/ml, about 9.6mg/ml, about 9.7 mg/ml, about 9.8 mg/ml, about 9.9 mg/ml, or about 10.0mg/ml in the oral liquid formulation. In some embodiments, thesuspension aid is present in about 4.0 mg/ml to about 6.0 mg/ml in theoral liquid formulation. In some embodiments, the suspension aid ispresent in about 6.0 mg/ml to about 8.0 mg/ml in the oral liquidformulation. In some embodiments, the suspension aid is hydroxypropylmethyl cellulose and is present in about 5.0 mg/ml in the oral liquidformulation. In some embodiments, the suspension aid is hydroxypropylmethyl cellulose and is present in about 7.5 mg/ml in the oral liquidformulation. In some embodiments, the suspension aid is hydroxypropylmethyl cellulose and is present in about 10 mg/ml in the oral liquidformulation.

In some embodiments, the suspension aid is present in about 10 mg/ml toabout 30 mg/ml in the oral liquid formulation. In other embodiments, thesuspension aid is present in about 10 mg/ml, about 11 mg/ml, about 12mg/ml, about 13 mg/ml, about 14 mg/ml, about 15 mg/ml, about 16 mg/ml,about 17 mg/ml, about 18 mg/ml, about 19 mg/ml, about 20 mg/ml, about 21mg/ml, about 22 mg/ml, about 23 mg/ml, about 24 mg/ml, about 25 mg/ml,about 26 mg/ml, about 27 mg/ml, about 28 mg/ml, about 29 mg/ml, or about30 mg/ml in the oral liquid formulation. In some embodiments, thesuspension aid is polyvinylpyrrolidone and is present in about 10 mg/mlin the oral liquid formulation. In some embodiments, the suspension aidis polyvinylpyrrolidone and is present in about 20 mg/ml in the oralliquid formulation. In some embodiments, the suspension aid ispolyvinylpyrrolidone and is present in about 30 mg/ml in the oral liquidformulation.

In some embodiments, the suspension aid is present in about 5 mg/ml toabout 15 mg/ml in the oral liquid formulation. In other embodiments, thesuspension aid is present in about 5.0 mg/ml, about 5.5 mg/ml, about 6.0mg/ml, about 6.5 mg/ml, about 7.0 mg/ml, about 7.5 mg/ml, about 8 mg/ml,about 8.5 mg/ml, about 9 mg/ml, about 9.5 mg/ml, about 10 mg/ml, about10.5 mg/ml, about 11 mg/ml, about 11.5 mg/ml, about 12 mg/ml, about 12.5mg/ml, about 13 mg/ml, about 13.5 mg/ml, about 14 mg/ml, about 14.5mg/ml, or about 15 mg/ml in the oral liquid formulation. In someembodiments, the suspension aid is Avicel® RC-591 and is present inabout 5 mg/ml in the oral liquid formulation. In some embodiments, thesuspension aid is Avicel® RC-591 and is present in about 7.5 mg/ml inthe oral liquid formulation. In some embodiments, the suspension aid isAvicel® RC-591 and is present in about 10 mg/ml in the oral liquidformulation. In some embodiments, the suspension aid is Avicel® RC-591and is present in about 15 mg/ml in the oral liquid formulation.

In some embodiments, the suspension aid is present in about 0.4% w/w toabout 6% w/w of the solids in the oral liquid formulation. In otherembodiments, the suspension aid is present in about 0.4% w/w, about 0.5%w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w,about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4%w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w,about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3%w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w,about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2%w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w,about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1%w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w,about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5%w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w,about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about5.9% w/w, or about 6% w/w of the solids in the oral liquid formulation.

In some embodiments, the suspension aid is present in about 20% w/w toabout 50% w/w of the solids in the oral liquid formulation. In otherembodiments, the suspension aid is present in about 20% w/w, about 20.5%w/w, about 21% w/w, about 21.5% w/w, about 22% w/w, about 22.5% w/w,about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w, about25% w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about 27% w/w,about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w, about29.5% w/w, about 30% w/w, about 30.5% w/w, about 31% w/w, about 31.5%w/w, about 32% w/w, about 32.5% w/w, about 33% w/w, about 33.5% w/w,about 34% w/w, about 34.5% w/w, about 35% w/w, about 35.5% w/w, about36% w/w, about 36.5% w/w, about 37% w/w, about 37.5% w/w, about 38% w/w,about 38.5% w/w, about 39% w/w, about 39.5% w/w, about 40% w/w, about41% w/w, about 41.5% w/w, about 42% w/w, about 42.5% w/w, about 43% w/w,about 43.5% w/w, about 44% w/w, about 44.5% w/w, about 45% w/w, about45.5% w/w, about 46% w/w, about 46.5% w/w, about 47% w/w, about 47.5%w/w, about 48% w/w, about 48.5% w/w, about 49% w/w, about 39.5% w/w, orabout 50% w/w of the solids in the oral liquid formulation.

In some embodiments, the suspension aid is present in about 40% w/w toabout 85% w/w of the solids in the oral liquid formulation. In otherembodiments, the suspension aid is present in about 40% w/w, about 41%w/w, about 42% w/w, about 43% w/w, about 44% w/w, about 45% w/w, about46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50% w/w,about 51% w/w, about 52% w/w, about 53% w/w, about 54% w/w, about 55%w/w, about 56% w/w, about 57% w/w, about 58% w/w, about 59% w/w, about60% w/w, about 61% w/w, about 62% w/w, about 63% w/w, about 64% w/w,about 65% w/w, about 66% w/w, about 67% w/w, about 68% w/w, about 69%w/w, about 70% w/w, about 71% w/w, about 72% w/w, about 73% w/w, about74% w/w, about 75% w/w, about 76% w/w, about 77% w/w, about 78% w/w,about 79% w/w, about 80% w/w, about 81% w/w, about 82% w/w, about 83%w/w, about 84% w/w, or about 85% w/w of the solids in the oral liquidformulation.

In some embodiments, the suspension aid is present in about 35% w/w toabout 55% w/w of the solids in the oral liquid formulation. In otherembodiments, the suspension aid is present in about 35% w/w, about 36%w/w, about 37% w/w, about 38% w/w, about 39% w/w, about 40% w/w, about41% w/w, about 42% w/w, about 43% w/w, about 44% w/w, about 45% w/w,about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50%w/w, about 51% w/w, about 52% w/w, about 53% w/w, about 54% w/w, orabout 55% w/w of the solids in the oral liquid formulation.

Antifoaming Agent in the Amlodipine Oral Liquid Formulations

Antifoaming agents are chemical additives that reduce and hinder theformation of foam in the preparation of an oral liquid formulation. Theterms antifoaming agent and defoamer are often used interchangeably.Commonly used agents are insoluble oils, polydimethylsiloxanes (e.g.,simethicone) and other silicones, certain alcohols, stearates andglycols. Simethicone is available as a pure material (100%) and incombination with other excipients to facilitate dispersion and handling.Common simethicone containing products include NuSil MED-342 (30% w/wsimethicone, solid), NuSil Med-340, Med-346, and Med-347 (100% silicone,liquid), Dow Corning® Q7-2587, 7-9245, and Medical Antifoam C (30%Simethicone Emulsion). The additive is used to prevent formation of foamor is added to break foam already formed. Antifoaming agents reducefoaming in the preparation of an oral liquid formulation which canresult in coagulation of aqueous dispersions.

In some embodiments, the amlodipine oral liquid formulation describedherein comprises an antifoaming agent. In some embodiments, theantifoaming agent is simethicone.

In some embodiments, the antifoaming agent is present in about 0.05mg/ml to about 1.0 mg/ml in the oral liquid formulation. In otherembodiments, the antifoaming agent is present in about 0.05 mg/ml, about0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml, about0.3 mg/ml, about 0.35 mg/ml, about 0.4 mg/ml, about 0.45 mg/ml, about0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about0.9 mg/ml, about 0.95 mg/ml, or about 1.0 mg/ml in the oral liquidformulation. In some embodiments, the antifoaming agent is present inabout 0.05 mg/ml to about 0.3 mg/ml in the oral liquid formulation. Insome embodiments, the antifoaming agent is present in about 0.1 mg/ml toabout 0.2 mg/ml in the oral liquid formulation. In some embodiments, theantifoaming agent is simethicone and is present in about 0.15 mg/ml inthe oral liquid formulation.

In some embodiments, the antifoaming agent is present in about 0.1% w/wto about 7% w/w of the solids in the oral liquid formulation. In otherembodiments, the antifoaming agent is present in about 0.1% w/w, about0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6%w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5%w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w,about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4%w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w,about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3%w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w,about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2%w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w,about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1%w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w,about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6%w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w,about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about6.9% w/w, or about 7% w/w of the solids in the oral liquid formulation.

Surfactants in the Amlodipine Oral Liquid Formulations

Surfactants are compounds that lower the surface tension (or interfacialtension) between two liquids or between a liquid and a solid. Mostcommonly, surfactants are classified according to polar head group. Anon-ionic surfactant has no charged groups in its head. The head of anionic surfactant carries a net positive, or negative charge. If thecharge is negative, the surfactant is more specifically called anionic;if the charge is positive, it is called cationic. If a surfactantcontains a head with two oppositely charged groups, it is termedzwitterionic. Anionic surfactants contain anionic functional groups attheir head, such as sulfate, sulfonate, phosphate, and carboxylates.Prominent alkyl sulfates include ammonium lauryl sulfate, sodium laurylsulfate (sodium dodecyl sulfate, SLS, or SDS), and the relatedalkyl-ether sulfates sodium laureth sulfate (sodium lauryl ether sulfateor SLES), and sodium myreth sulfate. Others include: docusate (dioctylsodium sulfosuccinate), perfluorooctanesulfonate (PFOS),perfluorobutanesulfonate, alkyl-aryl ether phosphates, alkyl etherphosphates. Cationic surfactant include pH-dependent primary, secondary,or tertiary amines such as octenidine dihydrochloride; and permanentlycharged quaternary ammonium salts such as cetrimonium bromide (CTAB),cetylpyridinium chloride (CPC), benzalkonium chloride (BAC),benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, anddioctadecyldimethylammonium bromide (DODAB). Zwitterionic (amphoteric)surfactants have both cationic and anionic centers attached to the samemolecule. The cationic part is based on primary, secondary, or tertiaryamines or quaternary ammonium cations. The anionic part can be morevariable and include sulfonates, as in the sultaines CHAPS(3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate) andcocamidopropyl hydroxysultaine. Betaines such as cocamidopropyl betainehave a carboxylate with the ammonium. The most common biologicalzwitterionic surfactants have a phosphate anion with an amine orammonium, such as the phospholipids phosphatidylserine,phosphatidylethanolamine, phosphatidylcholine, and sphingomyelins.Nonionic surfactants include fatty alcohols, cetyl alcohol, stearylalcohol, and cetostearyl alcohol, and oleyl alcohol. Also used asnonionic surfactants are polyethylene glycol alkyl ethers (such asoctaethylene glycol monododecyl ether, pentaethylene glycol monododecylether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (suchas decyl glucoside, lauryl glucoside, octyl glucoside), polyethyleneglycol octylphenyl ethers (such as Triton X-100), polyethylene glycolalkylphenyl ethers (such as nonoxynol-9), glycerol alkyl esters (such asglyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such aspolysorbate), sorbitan alkyl esters (such as Spans), cocamide MEA,cocamide DEA, dodecyldimethylamine oxide, block copolymers ofpolyethylene glycol and polypropylene glycol (such as poloxamers), andpolyethoxylated tallow amine (POEA). The most commonly used surfactantsare fatty acid esters of sorbitan polyethoxylates, i.e. polysorbate 20and polysorbate 80. The two differ only in the length of the aliphaticchain that imparts hydrophobic character to the molecules, C-12 andC-18, respectively. Polysorbate 80 is more surface-active and has alower critical micellar concentration than polysorbate 20.

In some embodiments, the amlodipine oral liquid formulation describedherein comprises a surfactant. In some embodiments, the surfactant ispolysorbate 80. In some embodiments, the amlodipine oral liquidformulation described herein does not comprise a surfactant.

In some embodiments, the surfactant, when present, is present in about0.1 mg/ml to about 3.0 mg/ml in the oral liquid formulation. In otherembodiments, the surfactant, when present, is present in about 0.1mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml, about 0.3mg/ml, about 0.35 mg/ml, about 0.4 mg/ml, about 0.45 mg/ml, about 0.5mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about 0.9mg/ml, about 0.95 mg/ml, about 1.0 mg/ml, about 1.1 mg/ml, about 1.15mg/ml, about 1.2 mg/ml, about 1.25 mg/ml, about 1.3 mg/ml, about 1.35mg/ml, about 1.4 mg/ml, about 1.45 mg/ml, about 1.5 mg/ml, about 1.55mg/ml, about 1.6 mg/ml, about 1.65 mg/ml, about 1.7 mg/ml, about 1.75mg/ml, about 1.8 mg/ml, about 1.85 mg/ml, about 1.9 mg/ml, about 1.95mg/ml, about 2.0 mg/ml, about 2.1 mg/ml, about 2.15 mg/ml, about 2.2mg/ml, about 2.25 mg/ml, about 2.3 mg/ml, about 2.35 mg/ml, about 2.4mg/ml, about 2.45 mg/ml, about 2.5 mg/ml, about 2.55 mg/ml, about 2.6mg/ml, about 2.65 mg/ml, about 2.7 mg/ml, about 2.75 mg/ml, about 2.8mg/ml, about 2.85 mg/ml, about 2.9 mg/ml, about 2.95 mg/ml, or about 3.0mg/ml in the oral liquid formulation. In some embodiments, thesurfactant, when present, is polysorbate 80 and is present in about 0.5mg/ml in the oral liquid formulation. In some embodiments, thesurfactant, when present, is polysorbate 80 and is present in about 1.0mg/ml in the oral liquid formulation. In some embodiments, thesurfactant, when present, is polysorbate 80 and is present in about 2.0mg/ml in the oral liquid formulation.

In some embodiments, the surfactant, when present is present in about 1%w/w to about 15% w/w of the solids in the oral liquid formulation. Inother embodiments, the surfactant, when present is present in about 1%,about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%,about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%,about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%,about 14%, about 14.5%, or about 15% of the solids in the oral liquidformulation.

In some embodiments, the surfactant, when present is present in about 1%w/w to about 5% w/w of the solids in the oral liquid formulation. Inother embodiments, the surfactant, when present is present in about 1%,about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%,about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%,about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%,about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%,about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%,about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%,about 4.7%, about 4.8%, about 4.9%, or about 5% of the solids in theoral liquid formulation.

Additional Excipients

In further embodiments, the amlodipine oral liquid formulation describedherein comprises additional excipients including, but not limited toflavoring agents, coloring agents and thickeners. Additional excipientssuch as bulking agents, tonicity agents and chelating agents are withinthe scope of the embodiments.

In another embodiment, the amlodipine oral liquid formulation comprisesa flavoring agent or flavorant to enhance the taste or aroma of theformulation in liquid form. Suitable natural or synthetic flavoringagents can be selected from standard reference books, for exampleFenaroli's Handbook of Flavor Ingredients, 3rd edition (1995).Non-limiting examples of suitable natural flavors, some of which canreadily be simulated with synthetic agents or combinations thereof,include almond, anise, apple, apricot, bergamot, blackberry,blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove,coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig,ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt,mandarin, molasses, nutmeg, mixed berry, orange, peach, pear,peppermint, pineapple, raspberry, rose, spearmint, strawberry,tangerine, tea, vanilla, wintergreen, etc. Also useful, particularlywhere the formulation is intended primarily for pediatric use, istutti-frutti or bubblegum flavor, a compounded flavoring agent based onfruit flavors. Presently preferred flavoring agents include anise,cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry),grape, bubblegum, vanilla, and mixed berry. Flavoring agents can be usedsingly or in combinations of two or more. In certain embodiments, theamlodipine oral liquid formulation comprises a flavoring agent.

In further embodiments, the amlodipine oral liquid formulation comprisesa coloring agent for identity and/or aesthetic purposes. Suitablecoloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20,FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, FD&C Green No. 5,FD&C Orange No. 5, caramel, ferric oxide and mixtures thereof.

Thickeners impart viscosity or weight to the resultant liquid forms fromthe amlodipine formulation described herein. Exemplary thickenersinclude dextrin, cellulose derivatives (carboxymethylcellulose and itssalts, ethylcellulose, hydroxyethyl cellulose, methylcellulose,hypromellose, and the like) starches, pectin, polyethylene glycol,polyethylene oxide, trehalose, certain silicates (magnesium aluminumsilicate, aluminum silicate, etc. such as Veegum, Bentonite, and Kaolin)and certain gums (xanthan gum, locust bean gum, etc.). In certainembodiments, the amlodipine oral liquid formulation comprises athickener.

In further embodiments, the amlodipine liquid formulation does notcomprise glycerol which may cause headache, stomach upset, and diarrhea.

Additional excipients are contemplated in the amlodipine oral liquidformulation embodiments. These additional excipients are selected basedon function and compatibility with the amlodipine liquid formulationsdescribed herein and may be found, for example in Remington: The Scienceand Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack PublishingCompany, 1995); Hoover, John E., Remington's Pharmaceutical Sciences,(Easton, Pa.: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L.,Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980);and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed(Lippincott Williams & Wilkins 1999), herein incorporated by referencein their entirety.

Stability

The amlodipine oral liquid formulations described herein are stable invarious storage conditions including refrigerated, ambient andaccelerated conditions. Stable as used herein refers to amlodipine oralliquid formulations having about 95% or greater of the initialamlodipine amount and/or about 5% w/w or less total impurities orrelated substances at the end of a given storage period. In someembodiment, the impurity is amlodipine USP impurity A (A.K.A EP impurityD):

The percentage of impurities is calculated from the amount of impuritiesrelative to the amount of amlodipine. Stability is assessed by HPLC orany other known testing method. In some embodiments, the stableamlodipine oral liquid formulations have about 5% w/w, about 4% w/w,about 3% w/w, about 2.5% w/w, about 2% w/w, about 1.5% w/w, about 1%w/w, or about 0.5% w/w total impurities or related substances. In otherembodiments, the stable amlodipine oral liquid formulations have about5% w/w total impurities or related substances. In yet other embodiments,the stable amlodipine oral liquid formulations have about 4% w/w totalimpurities or related substances. In yet other embodiments, the stableamlodipine oral liquid formulations have about 3% w/w total impuritiesor related substances. In yet other embodiments, the stable amlodipineoral liquid formulations have about 2% w/w total impurities or relatedsubstances. In yet other embodiments, the stable amlodipine oral liquidformulations have about 1% w/w total impurities or related substances.

At refrigerated condition, the amlodipine oral liquid formulationsdescribed herein are stable for at least 1 month, at least 2 months, atleast 3 months, at least 6 months, at least 9 months, at least 12months, at least 15 months, at least 18 months, at least 24 months, atleast 30 months and at least 36 months. In some embodiments,refrigerated condition is 5±5° C. In some embodiments, refrigeratedcondition is about 0° C., about 0.1° C., about 0.2° C., about 0.3° C.,about 0.4° C., about 0.5° C., about 0.6° C., about 0.7° C., about 0.8°C., about 0.9° C., about 1° C., about 1.1° C., about 1.2° C., about 1.3°C., about 1.4° C., about 1.5° C., about 1.6° C., about 1.7° C., about1.8° C., about 1.9° C., about 2° C., about 2.1° C., about 2.2° C., about2.3° C., about 2.4° C., about 2.5° C., about 2.6° C., about 2.7° C.,about 2.8° C., about 2.9° C., about 3° C., about 3.1° C., about 3.2° C.,about 3.3° C., about 3.4° C., about 3.5° C., about 3.6° C., about 3.7°C., about 3.8° C., about 3.9° C., about 4° C., about 4.1° C., about 4.2°C., about 4.3° C., about 4.4° C., about 4.5° C., about 4.6° C., about4.7° C., about 4.8° C., about 4.9° C., about 5° C., about 5.1° C., about5.2° C., about 5.3° C., about 5.4° C., about 5.5° C., about 5.6° C.,about 5.7° C., about 5.8° C., about 5.9° C., about 6° C., about 6.1° C.,about 6.2° C., about 6.3° C., about 6.4° C., about 6.5° C., about 6.6°C., about 6.7° C., about 6.8° C., about 6.9° C., about 7° C., about 7.1°C., about 7.2° C., about 7.3° C., about 7.4° C., about 7.5° C., about7.6° C., about 7.7° C., about 7.8° C., about 7.9° C., about 8° C., about8.1° C., about 8.2° C., about 8.3° C., about 8.4° C., about 8.5° C.,about 8.6° C., about 8.7° C., about 8.8° C., about 8.9° C., about 9° C.,about 9.1° C., about 9.2° C., about 9.3° C., about 9.4° C., about 9.5°C., about 9.6° C., about 9.7° C., about 9.8° C., about 9.9° C., or about10° C. At accelerated conditions, the amlodipine oral liquidformulations described herein are stable for at least 1 month, at least2 months, at least 3 months, at least 4 months, at least 5 months, atleast 6 months, at least 7 months, at least 8 months, at least 9 months,at least 10 months, at least 11 months, at least 12 months, at least 18months, or at least 24 months. Accelerated conditions for the amlodipineoral liquid formulations described herein include temperatures that areat or above ambient levels (25±5° C.). In some instances, an acceleratedcondition is at about 25° C., about 30° C., about 35° C., about 40° C.,about 45° C., about 50° C., about 55° C., or about 60° C. Acceleratedconditions for the amlodipine oral liquid formulations described hereinalso include relative humidity (RH) that are at or above ambient levels(55±10% RH). In other instances, an accelerated condition is above 55%RH, about 65% RH, about 70% RH, about 75% RH, or about 80% RH. Infurther instances, an accelerated condition is about 40° C. or 60° C. atambient humidity. In yet further instances, an accelerated condition isabout 40° C. at 75±5% RH humidity.

In some embodiments, the amlodipine oral liquid formulation is stablebetween about 5±5° C. and about 25±5° C. for at least 12 months. In oneembodiment, the amlodipine oral liquid formulation is stable at about5±5° C. for at least 12 months. In one embodiment, the amlodipine oralliquid formulation is stable at about 25±5° C. for at least 12 months.In one embodiment, the amlodipine oral liquid formulation is stable atabout 5±5° C. for at least 24 months. In one embodiment, the amlodipineoral liquid formulation is stable at about 25±5° C. for at least 24months.

Kits and Articles of Manufacture

For the amlodipine liquid formulations described herein, kits andarticles of manufacture are also described. Such kits can comprise acarrier, package, or container that is compartmentalized to receive oneor more containers such as vials, tubes, and the like, each of thecontainer(s) comprising one of the separate elements to be used in amethod described herein including an amlodipine liquid formulation.Suitable containers include, for example, bottles, vials, syringes, andtest tubes. The containers can be formed from a variety of materialssuch as glass or plastic.

A kit will typically comprise one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for an amlodipine liquid formulation described herein.Non-limiting examples of such materials include, but not limited to,buffers, diluents, filters, needles, syringes; carrier, package,container, vial and/or tube labels listing contents and/or instructionsfor use, and package inserts with instructions for use associated withan amlodipine liquid formulation. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

Method of Manufacturing

Disclosed herein is a process for preparing a stable amlodipine oralliquid formulation. In some embodiments, the stable amlodipine oralliquid formulation is in the form of a suspension. In some embodiments,the stable amlodipine oral liquid formulation comprises apharmaceutically acceptable salt of amlodipine which is very slightlysoluble in an aqueous media. In some embodiments, the stable amlodipineoral liquid formulation comprises a pharmaceutically acceptable salt ofamlodipine which is practically insoluble in an aqueous media.

Disclosed herein is a process for preparing a stable amlodipine oralliquid formulation, the process comprising mixing a first mixture with asecond mixture; the first mixture comprising: a pharmaceuticallyacceptable salt of amlodipine; optionally a salt comprising the counterions from a water soluble salt of amlodipine and a salt forming agent;one or more agent selected from the group consisting of preservativesand surfactants; and water; and the second mixture comprising: a buffer;optionally one or more agents selected from the group consisting offlavoring agents, sweetening agents, suspensions aids, and antifoamingagents; and water. In some embodiments, the first mixture comprises apharmaceutically acceptable salt of amlodipine; a preservative; asurfactant; and water. In some embodiments, the first mixture comprisesa pharmaceutically acceptable amlodipine salt; a preservative; andwater. In some embodiments, the first mixture is obtained by a processcomprising adding water to a first container; adding a water solublesalt of amlodipine to the first container; adding a salt forming agentto the first container; adding a preservative; optionally adding asurfactant to the first container; and stirring until a newpharmaceutically acceptable salt of amlodipine substantiallyprecipitates. In some embodiments, the second mixture comprises abuffer; optionally a flavoring agent; a sweetening agent; suspensionsaids; an antifoaming agent; and water. In some embodiments, the secondmixture is obtained by a process comprising adding water to a secondcontainer; adding a buffer to a second container; adding a sweeteningagent to a second container; optionally adding a flavoring agent to asecond container; adding an antifoaming agent to a second container;adding suspension aids to a second container; and stirring. In someembodiments, the preservative is sodium benzoate and the buffer is acitrate buffer. In some embodiments, the preservative is a paraben or amixture of parabens and the buffer is a phosphate buffer.

Disclosed herein is a process for preparing a stable amlodipine oralliquid formulation, the process comprising mixing a first mixture with asecond mixture; the first mixture comprising: amlodipine benzoate;sodium benzoate; optionally sodium besylate; optionally polysorbate 80;and water; and the second mixture comprising: citric acid; sodiumcitrate; sucralose; optionally a flavoring agent; hydroxypropylmethylcellulose; simethicone; silicon dioxide; and water. In someembodiments, the first mixture is obtained by a process comprisingadding water to a first container which is not stainless steel; addingamlodipine besylate to the first container; adding sodium benzoate tothe first container; optionally adding polysorbate 80 to the firstcontainer; and stirring until amlodipine benzoate substantiallyprecipitates. In some embodiments, the second mixture is obtained by aprocess comprising adding water to a second container; adding citricacid to the second container; adding sodium citrate to the secondcontainer; adding sucralose to the second container; optionally adding aflavoring agent to the second container; adding hydroxypropylmethylcellulose to the second container; adding simethicone to thesecond container; adding silicon dioxide to the second container; andstirring.

Disclosed herein is a process for preparing a stable amlodipine oralliquid formulation, the process comprising mixing a first mixture with asecond mixture; the first mixture comprising: amlodipine benzoate;sodium benzoate; polysorbate 80; optionally sodium besylate; and water;and the second mixture comprising: citric acid; sodium citrate;sucralose; optionally a flavoring agent; hydroxypropyl methylcellulose;simethicone; silicon dioxide; and water. In some embodiments, the firstmixture is obtained by a process comprising adding water to a firstcontainer which is not stainless steel; adding amlodipine besylate tothe first container; adding sodium benzoate to the first container;adding polysorbate 80 to the first container; and stirring untilamlodipine benzoate substantially precipitates. In some embodiments, thesecond mixture is obtained by a process comprising adding water to asecond container; adding citric acid to the second container; addingsodium citrate to the second container; adding sucralose to the secondcontainer; optionally adding the flavoring agent to the secondcontainer; adding hydroxypropyl methylcellulose to the second container;adding simethicone to the second container; adding silicon dioxide tothe second container; and stirring.

Disclosed herein is a process for preparing a stable amlodipine oralliquid formulation, the process comprising mixing a first mixture with asecond mixture; the first mixture comprising: amlodipine naphthalenesulfonate; sodium benzoate; optionally sodium besylate; optionallypolysorbate 80; and water; and the second mixture comprising: citricacid; sodium citrate; sucralose; optionally a flavoring agent;hydroxypropyl methylcellulose; simethicone; silicon dioxide; and water.In some embodiments, the first mixture is obtained by a processcomprising adding water to a first container which is not stainlesssteel; adding amlodipine besylate to the first container; adding sodiumnaphthalene-2-sulfonate to the first container; adding sodium benzoateto the first container; optionally adding polysorbate 80 to the firstcontainer; and stirring until amlodipine naphthalene sulfonatesubstantially precipitates. In some embodiments, the second mixture isobtained by a process comprising adding water to a second container;adding citric acid to the second container; adding sodium citrate to thesecond container; adding sucralose to the second container; optionallyadding the flavoring agent to the second container; adding hydroxypropylmethylcellulose to the second container; adding simethicone to thesecond container; adding silicon dioxide to the second container; andstirring. In some embodiments, the first mixture is obtained by aprocess comprising adding water to a first container which is notstainless steel; adding amlodipine besylate to the first container;adding sodium naphthalene-2-sulfonate to the first container; addingsodium benzoate to the first container; and stirring until amlodipinenaphthalene sulfonate substantially precipitates. In some embodiments,the second mixture is obtained by a process comprising adding water to asecond container; adding citric acid to the second container; addingsodium citrate to the second container; adding sucralose to the secondcontainer; optionally adding the flavoring agent to the secondcontainer; adding hydroxypropyl methylcellulose to the second container;adding simethicone to the second container; adding silicon dioxide tothe second container; and stirring. In some embodiments, the sodiumbenzoate is added to the second container. In some embodiments sodiumbenzoate is not added to the first container.

Disclosed herein is a process for preparing a stable amlodipine oralliquid formulation in a single container.

In some embodiments, the process for preparing a stable amlodipine oralliquid formulation in a single container comprises the formation of apharmaceutically acceptable salt of amlodipine; followed by addition ofone or more agents selected from the group consisting of preservatives,surfactants, flavoring agents, sweetening agents, suspensions aids, andantifoaming agents. In some embodiments, the pharmaceutically acceptablesalt of amlodipine is obtained by a process comprising adding water to acontainer, adding a buffer to the container; adding a water soluble saltof amlodipine to the container; adding a salt forming agent to thecontainer; and stirring until a new pharmaceutically acceptable salt ofamlodipine substantially precipitates. The process further comprisescooling the suspension of the new pharmaceutically acceptable salt ofamlodipine. The process further comprises adding optional componentsselected from preservatives, surfactants, flavoring agents, sweeteningagents, suspensions aids, and antifoaming agents. In some embodiments,the container is not stainless steel. In some embodiments, high shearmixing is used. In some embodiments, sonication is used.

In some embodiments, the process for preparing a stable amlodipine oralliquid formulation in a single container comprises the formation of apharmaceutically acceptable salt of amlodipine following the addition ofone or more agent selected from the group consisting of buffers,preservatives, surfactants, flavoring agents, sweetening agents,suspensions aids, and antifoaming agents. In some embodiments, processcomprises adding water to a container; adding a salt forming agent tothe container; optionally adding one or more agent selected from thegroup consisting of buffers, preservatives, surfactants, flavoringagents, sweetening agents, suspensions aids, and antifoaming agents tothe container; adding a water soluble salt of amlodipine to thecontainer; and stirring until a new pharmaceutically acceptable salt ofamlodipine substantially precipitates. In some embodiments, thecontainer is not stainless steel.

Methods of Treatment

Provided herein, in one aspect, are methods of treatment comprisingadministration of the amlodipine oral liquid formulations describedherein to a subject. In some embodiments, the amlodipine oral liquidformulations described herein treat hypertension in a subject.Hypertension as used herein includes both primary (essential)hypertension and secondary hypertension. In certain instances,hypertension is classified in cases when blood pressure values aregreater than or equal to 140/90 (systolic/diastolic) mm Hg in a subject.In certain instances, the amlodipine oral liquid formulations describedherein treat a subject having a blood pressure values are greater thanor equal to 140/90 mm Hg. In certain instances, the amlodipine oralliquid formulations described herein treat primary (essential)hypertension in a subject. In other instances, the amlodipine oralliquid formulations described herein treat secondary hypertension in asubject.

In other embodiments, the amlodipine oral liquid formulations describedherein treat prehypertension in a subject. Prehypertension as usedherein refers to cases where a subject's blood pressure is elevatedabove normal but not to the level considered to be hypertension. In someinstances, prehypertension is classified in cases when blood pressurevalues are 120-139/80-89 mm Hg. In certain instances, the amlodipineoral liquid formulations described herein treat a subject having bloodpressure values of 120-139/80-89 mm Hg.

In yet other embodiments, the amlodipine oral liquid formulationsdescribed herein are prophylactically administered to subjects suspectedof having, predisposed to, or at risk of developing hypertension. Insome embodiments, the administration of amlodipine oral liquidformulations described herein allow for early intervention prior toonset of hypertension. In certain embodiments, upon detection of abiomarker, environmental, genetic factor, or other marker, theamlodipine oral liquid formulations described herein areprophylactically administered to subjects.

In further embodiments, the amlodipine oral liquid formulationsdescribed herein treat Coronary Artery Disease (CAD). In someembodiments, the amlodipine oral liquid formulations described hereintreat chronic stable angina. In some embodiments, the amlodipine oralliquid formulations described herein treat vasospastic angina(Prinzmetal's or Variant angina). In some embodiments, the amlodipineoral liquid formulations described herein treat angiographicallydocumented coronary artery disease in patients without heart failure oran ejection fraction <40%.

Dosing

In one aspect, the amlodipine oral liquid formulations are used for thetreatment of diseases and conditions described herein. In addition, amethod for treating any of the diseases or conditions described hereinin a subject in need of such treatment, involves administration ofamlodipine oral liquid formulations in therapeutically effective amountsto said subject.

Dosages of amlodipine oral liquid formulations described can bedetermined by any suitable method. Maximum tolerated doses (MTD) andmaximum response doses (MRD) for amlodipine can be determined viaestablished animal and human experimental protocols as well as in theexamples described herein. For example, toxicity and therapeuticefficacy of amlodipine can be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, including, but notlimited to, for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between the toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratiobetween LD₅₀ and ED₅₀. Amlodipine dosages exhibiting high therapeuticindices are of interest. The data obtained from cell culture assays andanimal studies can be used in formulating a range of dosage for use inhuman. The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with minimal toxicity.The dosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. Additional relativedosages, represented as a percent of maximal response or of maximumtolerated dose, are readily obtained via the protocols.

In some embodiments, the amount of a given amlodipine oral liquidformulation that corresponds to such an amount varies depending uponfactors such as the particular amlodipine salt or form, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but can nevertheless be determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the liquidcomposition type, the condition being treated, and the subject or hostbeing treated.

In some embodiments, the amlodipine oral liquid formulations describedherein are provided in a dose per day from about 0.01 mg to 100 mg, fromabout 0.1 mg to about 80 mg, from about 1 to about 60, from about 2 mgto about 40 mg of amlodipine. In certain embodiments, the amlodipineoral liquid formulations described herein are provided in a daily doseof about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.4mg, about 0.6 mg, about 0.8 mg, about 1 mg, about 1.5 mg, about 2 mg,about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about70 mg, about 76, mg, about 80 mg, about 85 mg, about 90 mg or about 100mg, or any range derivable therein. In certain instances, the amlodipineoral liquid formulations described herein are provided in a dose per dayof about 1 mg. In certain instances, the amlodipine oral liquidformulations described herein are provided in a dose per day of about 2mg. In certain instances, the amlodipine oral liquid formulationsdescribed herein are provided in a dose per day of about 3 mg. Incertain instances, the amlodipine oral liquid formulations describedherein are provided in a dose per day of about 4 mg. In certaininstances, the amlodipine oral liquid formulations described herein areprovided in a dose per day of about 5 mg. In certain instances, theamlodipine oral liquid formulations described herein are provided in adose per day of about 6 mg. In certain instances, the amlodipine oralliquid formulations described herein are provided in a dose per day ofabout 7 mg. In certain instances, the amlodipine oral liquidformulations described herein are provided in a dose per day of about 8mg. In certain instances, the amlodipine oral liquid formulationsdescribed herein are provided in a dose per day of about 9 mg. Incertain instances, the amlodipine oral liquid formulations describedherein are provided in a dose per day of about 10 mg. In certaininstances, the amlodipine oral liquid formulations described herein areprovided in a dose per day of about 11 mg. In certain instances, theamlodipine oral liquid formulations described herein are provided in adose per day of about 12 mg. The dose per day described herein can begiven once per day or multiple times per day in the form of sub-dosesgiven b.i.d., t.i.d., q.i.d., or the like where the number of sub-dosesequal the dose per day.

In further embodiments, the daily dosages appropriate for the amlodipineoral liquid formulations described herein are from about 0.01 to about1.0 mg/kg per body weight. In one embodiment, the daily dosagesappropriate for the amlodipine oral liquid formulations are from about0.02 to about 0.8 mg/kg amlodipine per body weight. In anotherembodiment, the daily dosage appropriate for the amlodipine oral liquidformulations are from about 0.05 to about 0.6 mg/kg per body weight. Inanother embodiment, the daily dosage appropriate for the amlodipine oralliquid formulations is about 0.05 mg/kg, about 0.06 mg/kg, about 0.07mg/kg, about 0.08 mg/kg, about 0.10 mg/kg, about 0.15 mg/kg, about 0.20mg/kg, about 0.25 mg/kg, about 0.30 mg/kg, about 0.40 mg/kg, about 0.50mg/kg, or about 0.60 mg/kg.

In other embodiments, the amlodipine oral liquid formulations areprovided at the maximum tolerated dose (MTD) for amlodipine. In otherembodiments, the amount of the amlodipine oral liquid formulationsadministered is from about 10% to about 90% of the maximum tolerateddose (MTD), from about 25% to about 75% of the MTD, or about 50% of theMTD. In particular embodiments, the amount of the amlodipine oral liquidformulations administered is from about 5%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, orhigher, or any range derivable therein, of the MTD for amlodipine.

In further embodiments, the amlodipine oral liquid formulations areprovided in a dosage that is similar, comparable or equivalent to adosage of a known amlodipine tablet formulation. In other embodiments,the amlodipine oral liquid formulations are provided in a dosage thatprovides similar, comparable or equivalent pharmacokinetic parameters(e.g., AUC, C_(max), T_(max), C_(min), T_(1/2)) as a dosage of a knownamlodipine tablet formulation. Similar, comparable or equivalentpharmacokinetic parameters, in some instances, refer to within 80% to125%, 80% to 120%, 85% to 125%, 90% to 110%, or increments therein, ofthe given values. It should be recognized that the ranges can, but neednot be symmetrical, e.g., 85% to 105%.

Administration

Administration of an amlodipine oral liquid formulation is at a dosagedescribed herein or at other dose levels and formulations determined andcontemplated by a medical practitioner. In certain embodiments, theamlodipine oral liquid formulations described herein are administeredfor prophylactic and/or therapeutic treatments. In certain therapeuticapplications, the amlodipine oral liquid formulations are administeredto a patient already suffering from a disease, e.g., hypertension, in anamount sufficient to cure the disease or at least partially arrest orameliorate the symptoms, e.g., lower blood pressure. Amounts effectivefor this use depend on the severity of the disease, previous therapy,the patient's health status, weight, and response to the amlodipineformulations, and the judgment of the treating physician.Therapeutically effective amounts are optionally determined by methodsincluding, but not limited to, a dose escalation clinical trial.

In prophylactic applications, the amlodipine oral liquid formulationsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, e.g., hypertension. Such anamount is defined to be a “prophylactically effective amount or dose.”In this use, the precise amounts also depend on the patient's state ofhealth, weight, and the like. When used in a patient, effective amountsfor this use will depend on the risk or susceptibility of developing theparticular disease, previous therapy, the patient's health status andresponse to the amlodipine formulations, and the judgment of thetreating physician.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of an amlodipine oralliquid formulations described herein are administered chronically, thatis, for an extended period of time, including throughout the duration ofthe patient's life in order to ameliorate or otherwise control or limitthe symptoms of the patient's disease. In other embodiments,administration of an amlodipine oral liquid formulation continues untilcomplete or partial response of a disease.

In certain embodiments wherein a patient's status does improve, the doseof an amlodipine oral liquid formulation being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). In specific embodiments, the length ofthe drug holiday is between 2 days and 1 year, including by way ofexample only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days,12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days,120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days,320 days, 350 days, and 365 days. The dose reduction during a drugholiday is, by way of example only, by 10%-100%, including by way ofexample only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, and 100%.

In some embodiments, amlodipine oral liquid formulations describedherein are administered chronically. For example, in some embodiments,an amlodipine oral liquid formulation is administered as a continuousdose, i.e., administered daily to a subject. In some other embodiments,amlodipine oral liquid formulations described herein are administeredintermittently (e.g. drug holiday that includes a period of time inwhich the formulation is not administered or is administered in areduced amount).

In some embodiments, the amlodipine oral liquid formulation isadministered to a subject who is in a fasted state. A fasted staterefers to a subject who has gone without food or fasted for a certainperiod of time. General fasting periods include at least 4 hours, atleast 6 hours, at least 8 hours, at least 10 hours, at least 12 hours,at least 14 hours and at least 16 hours without food. In someembodiments, an amlodipine oral liquid formulation is administeredorally to a subject who is in a fasted state for at least 8 hours. Inother embodiments, an amlodipine oral liquid formulation is administeredto a subject who is in a fasted state for at least 10 hours. In yetother embodiments, an amlodipine oral liquid formulation is administeredto a subject who is in a fasted state for at least 12 hours. In otherembodiments, an amlodipine oral liquid formulation is administered to asubject who has fasted overnight.

In other embodiments, the amlodipine oral liquid formulation isadministered to a subject who is in a fed state. A fed state refers to asubject who has taken food or has had a meal. In certain embodiments, anamlodipine oral liquid formulation is administered to a subject in a fedstate 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal,20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50minutes post-meal, 1 hour post-meal, or 2 hours post-meal. In certaininstances, an amlodipine oral liquid formulation is administered to asubject in a fed state 30 minutes post-meal. In other instances, anamlodipine oral liquid formulation is administered to a subject in a fedstate 1 hour post-meal. In yet further embodiments, an amlodipine oralliquid formulation is administered to a subject with food.

In further embodiments described herein, an amlodipine oral liquidformulation is administered at a certain time of day for the entireadministration period. For example, an amlodipine oral liquidformulation can be administered at a certain time in the morning, in theevening, or prior to bed. In certain instances, an amlodipine oralliquid formulation is administered in the morning. In other embodiments,an amlodipine oral liquid formulation can be administered at differenttimes of the day for the entire administration period. For example, anamlodipine oral liquid formulation can be administered on 8:00 am in themorning for the first day, 12 pm noon for the next day oradministration, 4 pm in the afternoon for the third day oradministration, and so on.

Combinations

The treatment of certain diseases or conditions (e.g., hypertension,heart failure, myocardial infarction and the like) in a subject with anamlodipine oral liquid formulation described herein encompass additionaltherapies and treatment regimens with other agents in some embodiments.Such additional therapies and treatment regimens can include anothertherapy, e.g., additional anti-hypertensives, for treatment of theparticular disease or condition in some embodiments. Alternatively, inother embodiments, additional therapies and treatment regimens includeother agents used to treat adjunct conditions associated with thedisease or condition or a side effect from the amlodipine oral liquidformulation in the therapy.

Additional agents for use in combination with an amlodipine oral liquidformulation described herein include, but are not limited to, diuretics(loop, thiazide, potassium-sparing, and the like), beta blockers(metoprolol, propanolol, pronethalol, and the like), alpha blockers(phentolamine, phenoxybenzamine, tamsulosin, prazosin, and the like),mixed alpha and beta blockers (bucindolol, carvedilol, labetalol),calcium channel blockers (dihydropyridines such as nifedipine, etc.,diltiazem, verapamil and the like), angiotensin II receptor antagonists(saralasin, losartan, eprosartin, irbesartan, valsartan, and the like),other ACE inhibitors (enalapril, captopril, quinapril, ramipril,lisinopril, zofenopril, and the like), aldosterone antagonists(eplerenone, spironolactone and the like), vasodilators (hydralazine andthe like) and alpha-2 agonists (clonidine, moxonidine, guanabenz and thelike).

Certain Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments described herein, certain preferred methods, devices, andmaterials are now described.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “an excipient” is a referenceto one or more excipients and equivalents thereof known to those skilledin the art, and so forth.

The term “about” is used to indicate that a value includes the standardlevel of error for the device or method being employed to determine thevalue. The use of the term “or” in the claims is used to mean “and/or”unless explicitly indicated to refer to alternatives only or thealternatives are mutually exclusive, although the disclosure supports adefinition that refers to only alternatives and to “and/or.” The terms“comprise,” “have” and “include” are open-ended linking verbs. Any formsor tenses of one or more of these verbs, such as “comprises,”“comprising,” “has,” “having,” “includes” and “including,” are alsoopen-ended. For example, any method that “comprises,” “has” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

“Optional” or “optionally” may be taken to mean that the subsequentlydescribed structure, event or circumstance may or may not occur, andthat the description includes instances where the events occurs andinstances where it does not.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In some embodiments, a therapeutic agent such asamlodipine is directed to the treatment and/or the amelioration of,reversal of, or stabilization of the symptoms of hypertension describedherein.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic systemically or locally, as directly into oronto a target tissue, or to administer a therapeutic to a patientwhereby the therapeutic positively impacts the tissue to which it istargeted. Thus, as used herein, the term “administering”, when used inconjunction with an amlodipine formulation, can include, but is notlimited to, providing an amlodipine formulation into or onto the targettissue; providing an amlodipine formulation systemically to a patientby, e.g., oral administration whereby the therapeutic reaches the targettissue or cells. “Administering” a formulation may be accomplished byinjection, topical administration, and oral administration or by othermethods alone or in combination with other known techniques.

The term “animal” as used herein includes, but is not limited to, humansand non-human vertebrates such as wild, domestic and farm animals. Asused herein, the terms “patient,” “subject” and “individual” areintended to include living organisms in which certain conditions asdescribed herein can occur. Examples include humans, monkeys, cows,sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. Ina preferred embodiment, the patient is a primate. In certainembodiments, the primate or subject is a human. In certain instances,the human is an adult. In certain instances, the human is child. Infurther instances, the human is 12 years of age or younger. In certaininstances, the human is elderly. In other instances, the human is 60years of age or older. Other examples of subjects include experimentalanimals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.The experimental animal can be an animal model for a disorder, e.g., atransgenic mouse with hypertensive pathology. A patient can be a humansuffering from hypertension, or its variants or etiological forms.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The term “pharmaceutical composition” shall mean a compositioncomprising at least one active ingredient, whereby the composition isamenable to investigation for a specified, efficacious outcome in amammal (for example, without limitation, a human). Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

A “therapeutically effective amount” or “effective amount” as usedherein refers to the amount of active compound or pharmaceutical agentthat elicits a biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includes one ormore of the following: (1) preventing the disease; for example,preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display the pathology or symptomatology of the disease,(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and (3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology). As such,a non-limiting example of a “therapeutically effective amount” or“effective amount” of a formulation of the present disclosure may beused to inhibit, block, or reverse the activation, migration, orproliferation of cells or to effectively treat hypertension orameliorate the symptoms of hypertension.

The terms “treat,” “treated,” “treatment,” or “treating” as used hereinrefers to both therapeutic treatment in some embodiments andprophylactic or preventative measures in other embodiments, wherein theobject is to prevent or slow (lessen) an undesired physiologicalcondition, disorder or disease, or to obtain beneficial or desiredclinical results. For the purposes described herein, beneficial ordesired clinical results include, but are not limited to, alleviation ofsymptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. A prophylactic benefit oftreatment includes prevention of a condition, retarding the progress ofa condition, stabilization of a condition, or decreasing the likelihoodof occurrence of a condition. As used herein, “treat,” “treated,”“treatment,” or “treating” includes prophylaxis in some embodiments.

The terms “precipitate,” “precipitates,” or “precipitation” as usedherein, refers to the creation of a new solid phase comprising one ormore chemical entities from solution. Those of ordinary skill in the artwill understand and appreciate that the solid phase may exist incrystalline and/or amorphous forms and that crystalline forms mayinclude, but are not limited to, polymorphs, cocrystals, ioniccocrystals, ionic cocrystal solvates, salts, solvated salts andsolvates.

The terms “substantially precipitate,” “substantially precipitates” or“substantial precipitation” as used herein, refers to an amount ofprecipitation that is detectable, directly or indirectly, by techniquesknown to a person of ordinary skill in the art. Examples of techniquesmay include, but are not limited to, visual inspection of solutions todetermine changes in solution opaqueness/transparency, Focused BeamReflectance Measurement (FBRM) technology, Infrared Spectroscopy, RamanSpectroscopy, UV spectroscopy and turbidity analysis.

The terms “very slightly soluble” or “practically insoluble” as usedherein, refers to a concentration of less than about 0.6 mg/mL,preferably of less than about 0.2 mg/mL, and most preferably of lessthan about 0.05 mg/mL.

EXAMPLES Example 1. Formation of Amlodipine Salt Crystals in the Absenceor Presence of a Magnetic Stir Bar

(1A) Purified water (200 ml) was added to a 400 ml glass containerfitted with overhead rotational stirring using a PTFE(polytetrafluoroethylene) coated 2″ diameter impeller and shaft.Stirring was initiated at 250 rpm and anhydrous citric acid (110 mg) wasadded and dissolved. Amlodipine besylate (278 mg) was then addedfollowed by 1000 mg sodium benzoate. After 25 minutes, the stirringspeed was increased to 450 rpm for 45 additional minutes.

Results: No precipitate of amlodipine benzoate salt appeared until after1 hour of stirring. The particles were large, >100 microns in length.

(1B) The procedure in example (1A) was repeated with the exception thata magnetic stir bar was placed in the glass container in addition to theoverhead stirrer. No external magnetic stirring apparatus was present,only the stir bar. The stirring speed was maintained at 250 rpm.

Results: Amlodipine benzoate salt precipitated after 3 minutes ofstirring. The particles were small, at <50 microns in length.

(1C) Purified water (100 ml) was added to a 250 ml glass containerfitted with overhead rotational stirring using a PTFE(polytetrafluoroethylene) coated 2″ diameter impeller and shaft.Stirring was initiated at 275 rpm and polysorbate 80 (1.0 grams) wasadded and dissolved. Amlodipine besylate (1.39 grams) was added andallowed to disperse, then sodium benzoate (5.0 grams) was added. Thesuspension was stirred for 30 minutes after the sodium benzoate additionthen the stirring was stopped and a sample taken for microscopicevaluation.

Results: A precipitate appeared in the suspension that was primarilylarge rod-shaped crystals, >100 microns in length.

(1D) The procedure in example (1C) was repeated with the exception thata magnetic stir bar was placed in the glass container in addition to theoverhead stirrer. No external magnetic stirring apparatus was present,only the stir bar. The overhead stirring speed was maintained at 275rpm.

Results: Amlodipine benzoate salt precipitated after ˜3 minutes ofstirring. The particles were small and needle-shaped, at <50 microns inlength.

Example 2. Concentration Effect on Amlodipine Salt Crystal Formationwith Non-Magnetic Stirring

(2A) Purified water (50 ml) was added to a glass container fitted withoverhead rotational stirring using a PTFE coated 2″ diameter impellerand shaft. Stirring was initiated at 250 rpm and 2500 mg sodium benzoatewere added and dissolved. Amlodipine besylate (695 mg) was then addedfollowed by 275 mg anhydrous citric acid. This solution is equivalent topreparing the crystals using a water amount of 10% of a finalformulation weight.

Results: Amlodipine benzoate salt began precipitating immediately asparticles <−50 micron.

(2B) Purified water (150 ml) was added to a glass container fitted withoverhead rotational stirring using a PTFE coated impeller and shaft.Stirring was initiated at 250 rpm and 2500 mg sodium benzoate were addedand dissolved. Amlodipine besylate (695 mg) was then added followed by275 mg anhydrous citric acid. This solution is equivalent to preparingthe crystals using a water amount of 30% of a final formulation weight.

Results: Amlodipine benzoate salt began precipitating immediately asparticles <−50 micron.

(2C) Purified water (250 ml) was added to a glass container fitted withoverhead rotational stirring using a PTFE coated impeller and shaft.Stirring was initiated at 250 rpm and 2500 mg sodium benzoate were addedand dissolved. Amlodipine besylate (695 mg) was then added followed by275 mg anhydrous citric acid. This solution is equivalent to preparingthe crystals using a water amount of 50% of a final formulation weight.

Results: Amlodipine benzoate salt began precipitating, then dissolved,and finally re-precipitated as large particles (>50 microns) after ˜1hour.

(2D) Purified water (45 ml) was added to a 250 ml glass container fittedwith overhead rotational stirring using a PTFE coated 2″ diameterimpeller and shaft. Stirring was initiated at 250 rpm and 500 mg of a30% w/w simethicone powder were added and dissolved. Sodium benzoate(5000 mg) was added and dissolved and then amlodipine besylate (1390 mgin 5 ml water) was added. This solution is equivalent to preparing thecrystals using a water amount of 5% of a final formulation weight.

Results: Amlodipine benzoate salt precipitated immediately as very fineparticles that caked on the stirrer and did not disperse easily.

(2E) Purified water (90 ml) was added to a 250 mL HDPE container fittedwith overhead rotational stirring using a PTFE coated 2″ diameterimpeller and shaft. Stirring was initiated at 250 rpm and 500 mg of a30% w/w simethicone powder were added and dissolved. Sodium benzoate(5000 mg) was added and dissolved and then amlodipine besylate (1390 mgin 10 ml water) was added. This solution is equivalent to preparing thecrystals using a water amount of 10% of a final formulation weight.

Results: Amlodipine benzoate salt precipitated rapidly as smallparticles that dispersed easily.

(2F) Purified water (95 ml) was added to a 250 ml glass container fittedwith overhead rotational stirring using a PTFE coated 2″ diameterimpeller and shaft. Stirring was initiated at 250 rpm and 250 mg of a30% w/w simethicone powder were added and dissolved. Sodium benzoate(2500 mg) was added and dissolved and then amlodipine besylate (695 mgin 5 mL water) was added. This solution is equivalent to preparing thecrystals using a water amount of 20% of a final formulation weight.

Results: Amlodipine benzoate salt precipitated rapidly as smallparticles with some agglomeration.

Example 3

Amlodipine compositions were prepared using a process in which thepreferred amlodipine salt is formed in one container, another part ofthe formulation was prepared in a second container, and the contents ofthe first container and the second container were combined.

(3A) Purified water (approximately 10% of the final formulation weight)was added to a polyethylene first vessel (e.g., LLPD) fitted withmagnetic stirring. Stirring was initiated and polysorbate 80 was addedand dispersed in the solution. Amlodipine was then added with stirringuntil it was well dispersed, followed by the addition of the saltforming agent (e.g., sodium benzoate or sodium naphthalene-2-sulfonate).Stirring was continued for approximately 30 minutes after the additionof the salt forming agent.

Purified water (approximately 80% of the final formulation weight) wasadded to a stainless steel second vessel fitted with overhead rotationalstirring using a shaft and impeller. Stirring was initiated and thefollowing components were added individually with sufficient stirringafter each addition, to ensure each component was dissolved (citricacid, sodium citrate, sucralose, flavoring agent, hypromellose) or welldispersed (simethicone, silicon dioxide). High shear mixing was usedduring and after the addition of the hypromellose to facilitatedispersion and solubilization of this component.

The contents of the first vessel were then transferred to the secondvessel with stirring. Additional water was added to the second vessel tobring its weight to approximately 98% of the final formulation weight.The pH of the solution was measured and if required, adjusted to thedesired pH, then the solution was brought to the final weight withpurified water.

(3B) Purified water (approximately 10% of the final formulation weight)was added to a glass vessel fitted with magnetic stirring. Stirring wasinitiated and simethicone was added and dispersed in the solution. Thesalt forming agent was then added and dissolved. Amlodipine wasdispersed in purified water (approximately 1% of the final formulationweight) and the resulting liquid slowly added to the first vessel withstirring. Stirring was continued for approximately 30 minutes after theaddition of the amlodipine.

Purified water (approximately 22% of the final formulation weight) wasadded to a second glass vessel fitted with magnetic stirring. The waterwas heated to approximately 70° C. and silicone dioxide and hypromellosewere added with stirring. The heating was discontinued and an equalportion of cold water was added to the second vessel. Stirring wascontinued and sucralose and flavor were added and dissolved. Purifiedwater (approximately 6% of the final formulation weight) was then added.

The solutions from the two vessels were combined with stirring. Thevessels were rinsed with purified water (approximately 20% of the finalformulation weight) and the rinses added to the formulation. The pH waschecked, and as needed adjusted to pH 4.9 with a solution of citric acid(1.1 g anhydrous citric acid in 50 ml purified water). The solution wasbrought to final weight with purified water and mixed with high shearmixing.

(3C) Purified water (approximately 10% of the final formulation weight)was added to a first glass vessel fitted with magnetic stirring.Stirring was initiated and one-half of the simethicone and nine-tenthsof the salt forming agent were added. Amlodipine was then added overabout 5 minutes. Stirring was continued for approximately 30 minutesafter the addition of the amlodipine was completed.

Purified water (approximately 70% of the final formulation weight) wasadded to a second glass vessel fitted with magnetic stirring. Theremaining one-half of the simethicone, the remaining one-tenth of thesalt forming agent, sucralose, silicon dioxide, flavor, and hypromellosewere added to the vessel with stirring. High shear mixing was used afterthe addition of the hypromellose to facilitate dispersion andsolubilization of this component.

The contents of the first vessel were then transferred to the secondvessel with stirring. Additional water was added to the second vessel tobring its weight to approximately 90% of the final formulation weight.The formulation was again subjected to high shear mixing, and thenallowed to deaerate. The preparation was brought to final weight withpurified water and mixed. The pH of the solution was measured and asrequired, adjusted to the desired pH with anhydrous citric acid.

Example 4

Amlodipine compositions were prepared using a process in which thepreferred amlodipine salt is formed in one container, and thentransferred to a second container for the remaining process.

Purified water (approximately 10% of the final formulation weight) wasadded to a HDPE vessel fitted with a magnetic stirrer. Stirring wasinitiated and simethicone was added and dispersed in the solution. Thesalt forming agent was then added with stirring followed by the additionof amlodipine dispersed in purified water (approximately 1% of the finalformulation weight). Stirring was continued for approximately 30 minutesafter the addition of the amlodipine.

The preparation was transferred to a stainless steel vessel andadditional purified water (approximately 45% of the final formulationweight) was added to the vessel. Stirring was initiated and thefollowing components were added individually with stirring; citric acid,sucralose, silicon dioxide, flavor, and hypromellose. High shear mixingwas used after the addition of the hypromellose to facilitate dispersionand solubilization. Purified water (30% of the final formulation weight)was added with stirring and the preparation was allowed to deaerate. Thepreparation was brought to final weight with purified water and mixed.The pH was measured.

Example 5

Amlodipine compositions were prepared using processes in which thepreferred amlodipine salt is formed in a small portion of the finalvolume in one container, and then additional components are added to thesame container to complete the process.

(5A) Purified water (approximately 10% of the final formulation weight)was added to a glass vessel fitted with magnetic stirring. Stirring wasinitiated and simethicone was added and dispersed in the solution. Thesalt forming agent was then added with stirring followed by the additionof amlodipine. Stirring was continued for approximately 30 minutes afterthe addition of the amlodipine.

Additional purified water (approximately 85% of the final formulationweight) was added to the vessel. Stirring was initiated and thefollowing components were added individually with stirring; citric acid,sodium citrate, sucralose, silicon dioxide, flavor, and hypromellose.High shear mixing was used after the addition of the hypromellose tofacilitate dispersion and solubilization, then the preparation wasallowed to deaerate. The pH was checked and adjusted if necessary, andthe preparation was brought to final weight with purified water.

(5B) Polysorbate 80 was added to a glass vessel fitted with magneticstirring. Purified water (approximately 10% of the final formulationweight) was added and stirring was initiated to ensure dispersion of thepolysorbate in the solution. Amlodipine was then added with stirringuntil it was well dispersed, followed by the addition of the saltforming agent. Stirring was continued for approximately 30 minutes afterthe addition of the salt forming agent.

Additional purified water (approximately 85% of the final formulationweight) was added to the vessel. Stirring was initiated and thefollowing components were added individually with stirring; citric acid,sodium citrate, sucralose, silicon dioxide, flavor, simethicone andhypromellose. High shear mixing was used after the addition of thehypromellose to facilitate dispersion and solubilization, then thepreparation was allowed to deaerate. The pH was checked and adjusted ifnecessary, and the preparation was brought to final weight with purifiedwater.

Example 6

Amlodipine compositions were prepared using processes in which thepreferred amlodipine salt is formed in one container in a volume greaterthan one-half of the final volume, and then additional components wereadded to the same container to complete the process.

(6A) Purified water (approximately 90% of the final formulation weight)was added to a glass vessel fitted with magnetic stirring. Stirring wasinitiated and citric acid was added and dissolved in the solution,followed by amlodipine, followed by the salt forming agent. The solutionwas stirred for approximately 30 minutes to allow formation of theamlodipine salt. The solution was then cooled to 2-8° C. for 1 hour withcontinued stirring. Sucralose, silicon dioxide, simethicone, povidonefor some formulations, and hypromellose were added with stirring. Highshear mixing was applied to the formulation after the hypromelloseaddition. The formulation was then stirred for 30 minutes, brought tofinal weight with purified water, and stirred for another 30 minutes.

(6B) Purified water (approximately 90% of the final formulation weight)was added to a glass vessel fitted with magnetic stirring. Stirring wasinitiated and citric acid was added and dissolved in the solution,followed by sodium citrate, amlodipine, then the salt forming agent. Thesolution was stirred for approximately 30 minutes to allow formation ofthe amlodipine salt. Sodium benzoate, sucralose, silicon dioxide,simethicone, (flavor and color in some formulations) and hypromellosewere added with stirring. High shear mixing was applied to theformulation after the hypromellose addition. The formulation was thenstirred for 30 minutes, brought to final weight with purified water, andstirred for another 30 minutes.

(6C) Purified water (approximately 90% of the final formulation weight)was added to a glass vessel fitted with magnetic stirring. Stirring wasinitiated and citric acid was added and dissolved in the solution,followed by amlodipine, then the salt forming agent. The solution wasstirred for approximately 30 minutes to allow formation of theamlodipine salt. The solution was then cooled to 2-8° C. for 1 hour withcontinued stirring. Sucralose, silicon dioxide, simethicone and povidonewere added with stirring. The formulation was then stirred for 30minutes, brought to final weight with purified water, and stirred foranother 30 minutes.

(6D) Purified water (approximately 90% of the final formulation weight)was added to a glass vessel fitted with magnetic stirring. Stirring wasinitiated and hypromellose was added and dissolved in the water withhigh shear mixing. Citric acid, salt forming agent, sucralose,simethicone, flavoring agent and color in some preparations, were thenadded with stirring. The solution was brought to its final weight withpurified water, and the amlodipine was added with stirring. The solutionwas stirred for approximately 30 minutes to allow formation of theamlodipine salt.

(6E) Purified water (approximately 90% of the final formulation weight)was added to a glass vessel fitted with magnetic stirring. Stirring wasinitiated and mannitol was added and dissolved in the solution, followedby hypromellose, citric acid, salt forming agent, sucralose,simethicone, silicon dioxide, and in some formulations, a flavor. Thesolution was brought to its final weight with purified water, and theamlodipine was added with stirring. In some preparations, theformulation was subjected to ultrasonic energy (sonication) and in somepreparations the formulation was mixed with high shear mixing. Thesolution was then stirred for approximately 30 minutes to allowformation of the amlodipine salt.

Example A: Effect of pH on the Formation of Degradants in AmlodipineFormulations

Formulations were prepared containing Amlodipine according to Table A-1.Each formulation was dispensed into screw-capped high densitypolyethylene (HDPE) bottles and stored at both 5° C. and ambienttemperature. Samples were removed periodically and analyzed by astability indicating high performance liquid chromatography (HPLC)method for content of amlodipine and any degradants.

The HPLC method provided separation of amlodipine, amlodipine degradantsand formulation components on a C18 column with a gradient program usingmobile phases containing 0.1% trifluoroacetic acid (TFA) in water, and0.1% TFA in acetonitrile flowing at 1 mL/min. Detection was by UVabsorbance at 237 nm for amlodipine and its degradants. Any unknownimpurities were reported by their relative retention time (RRT) toamlodipine.

TABLE A-1 Composition (in mg/ml) of Amlodipine Formulations at VaryingpH Levels Formulation Component A1 A2 A3 A4 A5 A6 A7 A8 Amlodipinebesylate ^(a) 1.39 1.39 1.39 1.39 1.39 1.39 1.39 1.39 Mannitol 90.00 — —— — — — — Hypromellose K750 5.00 — — — — — — — Citric acid, anhydrous3.42 1.35 0.84 0.53 0.36 0.31 0.23 0.17 Sodium citrate, dihydrate — — —— — 0.36 0.47 0.55 Sodium benzoate 5.00 5.00 5.00 5.00 5.00 5.00 5.005.00 Sucralose/maltodextrin 4.00 — — — — — — — Sucralose — 0.70 0.700.70 0.70 0.70 0.70 0.70 Simethicone 0.15 0.15 0.15 0.15 0.15 0.15 0.150.15 Silicon dioxide 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 Artificialcherry flavor — 0.50 0.50 0.50 0.50 0.50 0.50 0.50 Hypromellose K1500 —5.00 5.00 5.00 5.00 5.00 5.00 5.00 Water q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. pH 3.98 4.51 4.71 4.90 5.09 5.31 5.54 5.75 ^(a) = equivalentto 1 mg/ml Amlodipine

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at 5° C. are provided in Table A-2. The resultsshow a decrease in total impurities as pH is increased from 4.0 to 5.7.

TABLE A-2 Assay and Primary Degradants Present in the FormulationsFormulation A1 A2 A3 A4 A5 A6 A7 A8 Weeks Amlodipine (% initial) Initial100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 4 97.77 96.6199.30 99.99 100.96 99.20 101.11 96.49 8 97.47 97.32 104.37 100.07 101.33100.58 98.10 97.04 12 97.88 97.41 102.28 102.09 101.88 100.59 100.7496.38 26 95.14 97.02 100.80 99.69 105.89 102.46 102.01 98.37 52 96.0297.16 100.08 101.26 101.94 100.40 99.96 97.34 78 98.24 98.37 101.86100.40 101.93 107.40 99.59 99.08 104 97.32 98.02 99.66 109.83 102.00101.79 100.25 97.37 Weeks USP Impurity A/EP Impurity D (wt % ofAmlodipine) Initial 0.06 0.02 0.03 0.00 0.03 0.00 0.00 0.00 4 0.08 0.050.03 0.04 0.04 0.00 0.02 0.04 8 0.12 0.01 0.01 0.01 0.01 0.04 0.01 0.0312 0.13 0.17 0.02 0.02 0.03 0.05 0.02 0.04 26 0.15 0.04 0.04 0.04 0.050.05 0.04 0.04 52 0.15 0.07 0.06 0.06 0.06 0.07 0.06 0.06 78 0.27 0.080.07 0.07 0.06 0.10 0.06 0.07 104 0.33 0.06 0.05 0.04 0.04 0.05 0.040.04 Weeks Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.02 0.00 0.000.00 0.00 0.00 0.00 0.00 4 0.02 0.00 0.01 0.00 0.00 0.01 0.00 0.00 80.06 0.02 0.02 0.01 0.01 0.00 0.00 0.00 12 0.04 0.04 0.03 0.02 0.02 0.010.01 0.01 26 0.07 0.08 0.07 0.05 0.04 0.04 0.03 0.02 52 0.11 0.13 0.130.12 0.10 0.09 0.06 0.04 78 0.16 0.21 0.20 0.18 0.15 0.14 0.10 0.06 1040.22 0.26 0.25 0.24 0.20 0.18 0.13 0.08 Weeks Total Impurities (wt % ofAmlodipine) Initial 0.23 0.07 0.06 0.03 0.08 0.06 0.06 0.08 4 0.28 0.110.09 0.09 0.08 0.04 0.06 0.14 8 0.66 0.09 0.09 0.07 0.09 0.07 0.06 0.1012 0.35 0.34 0.12 0.08 0.09 0.10 0.07 0.09 26 0.42 0.25 0.21 0.18 0.170.15 0.12 0.10 52 0.64 0.41 0.35 0.31 0.33 0.33 0.26 0.24 78 0.84 0.530.46 0.38 0.33 0.40 0.27 0.25 104 1.07 0.65 0.61 0.51 0.44 0.36 0.310.28

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at ambient temperature are provided in Table A-3.The results show a decrease in total impurities as pH is increased from4.0 to 5.7.

TABLE A-3 Assay and Primary Degradants Present in the FormulationsFormulation A1 A2 A3 A4 A5 A6 A7 A8 Weeks Amlodipine (% initial) Initial100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 2 89.38 98.81102.36 99.31 102.33 102.05 101.23 101.34 4 90.71 97.05 99.80 100.54105.81 101.27 99.14 98.06 6 85.22 95.86 102.42 101.22 100.86 102.45100.42 97.03 8 83.75 97.13 99.80 101.38 103.48 101.81 100.14 101.44 1279.33 96.28 100.33 100.61 103.18 101.61 100.90 97.50 26 — 91.68 96.9798.87 101.72 101.53 100.27 99.20 Weeks USP Impurity A/EP Impurity D (wt% of Amlodipine) Initial 0.06 0.02 0.03 0.00 0.03 0.00 0.00 0.00 2 0.300.05 0.05 0.05 0.04 0.03 0.01 0.04 4 0.43 0.08 0.08 0.07 0.07 0.06 0.060.06 6 0.65 0.05 0.05 0.03 0.04 0.10 0.05 0.05 8 0.79 0.05 0.04 0.030.04 0.10 0.17 0.09 12 1.03 0.06 0.05 0.05 0.04 0.14 0.12 0.13 26 — 0.270.21 0.20 0.18 0.26 0.23 0.24 Weeks Impurity RRT 0.97 (wt % ofAmlodipine) Initial 0.02 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 0.29 0.120.10 0.07 0.05 0.03 0.03 0.01 4 0.43 0.25 0.20 0.15 0.11 0.07 0.05 0.046 0.58 0.33 0.28 0.22 0.16 0.13 0.10 0.06 8 0.67 0.40 0.35 0.29 0.220.18 0.11 0.07 12 0.73 0.47 0.43 0.38 0.32 0.25 0.17 0.10 26 — 0.51 0.480.45 0.41 0.37 0.30 0.21 Weeks Total Impurities (wt % of Amlodipine)Initial 0.23 0.07 0.06 0.03 0.08 0.06 0.06 0.08 2 1.19 0.32 0.29 0.230.17 0.15 0.09 0.13 4 1.78 0.60 0.49 0.39 0.37 0.24 0.24 0.30 6 2.410.75 0.62 0.50 0.39 0.47 0.37 0.30 8 2.43 0.94 0.75 0.60 0.53 0.50 0.490.36 12 3.77 1.29 0.94 0.76 0.73 0.72 0.58 0.49 26 — 1.85 1.47 1.23 1.181.21 1.05 0.95

Example B. Effect of Benzoate Concentration on the Stability ofAmlodipine Formulations

Formulations were prepared containing Amlodipine according to Table B-1.Each formulation was dispensed into screw-capped HDPE bottles and storedat ambient temperature. Formulations B6, B7, and B8 were also stored at5° C. Samples were removed periodically and analyzed using the HPLCmethod in Example A.

TABLE B-1 Composition (in mg/ml) of Amlodipine Formulations at VaryingBenzoate Levels Formulation Component B1 B2 B3 B4 B5 B6 B7 B8 Amlodipinebesylate ^(a) 1.39 1.39 1.39 1.39 1.39 1.39 1.39 1.39 Hypromellose K750— — — — — 5.00 5.00 5.00 Citric acid, anhydrous ^(b) ^(b) ^(b) ^(b) ^(b)0.55 0.90 1.15 Sodium benzoate 1.00 2.00 3.00 4.00 5.00 5.00 7.50 10.00Sucralose 0.70 0.70 0.70 0.70 0.70 0.70 0.70 0.70 Simethicone 0.15 0.150.15 0.15 0.15 0.15 0.15 0.15 Silicon dioxide 0.50 0.50 0.50 0.50 0.50 —— — Artificial cherry 0.50 0.50 0.50 0.50 0.50 — — 0.50 flavorHypromellose K1500 5.00 5.00 5.00 5.00 5.00 — — — Red 40 Al lake color —— — — — — — 0.015 Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH 4.854.89 4.89 4.89 4.89 4.88 4.84 4.87 ^(a) = equivalent to 1 mg/mlAmlodipine ^(b) = adjusted pH to 4.9 with a solution containing 1.1 gcitric acid in 50 ml purified water before final dilution.

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at 5° C. are provided in Table B-2.

TABLE B-2 Assay and Primary Degradants Present in the FormulationsFormulation Weeks B6 B7 B8 Amlodipine (% initial) Initial 100.00 100.00100.00 2 97.56 99.22 98.15 4 97.18 98.00 98.18 6 99.13 99.04 97.28 898.81 98.44 98.17 12 99.17 98.80 98.80 26 99.89 97.03 97.42 52 96.3498.04 97.19 78 98.10 99.20 99.07 104 97.33 98.59 97.56 USP Impurity A/EPImpurity D (wt % of Amlodipine) Initial 0.03 0.00 0.04 2 0.03 0.02 0.024 0.02 0.03 0.03 6 0.03 0.02 0.02 8 0.03 0.04 0.03 12 0.04 0.03 0.02 260.05 0.03 0.04 52 0.04 0.03 0.03 78 0.11 0.09 0.09 104 0.13 0.10 0.10Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 2 0.000.00 0.00 4 0.01 0.01 0.01 6 0.02 0.01 0.01 8 0.02 0.02 0.01 12 0.050.04 0.03 26 0.10 0.08 0.07 52 0.19 0.15 0.12 78 0.28 0.25 0.21 104 0.350.32 0.27 Total Impurities (wt % of Amlodipine) Initial 0.10 0.09 0.15 20.08 0.08 0.07 4 0.07 0.07 0.07 6 0.10 0.07 0.09 8 0.10 0.09 0.08 120.13 0.11 0.10 26 0.22 0.17 0.17 52 0.37 0.30 0.24 78 0.54 0.44 0.39 1040.73 0.58 0.52

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at ambient temperature are provided in Table B-3.

TABLE B-3 Assay and Primary Degradants Present in the FormulationsFormulation B1 B2 B3 B4 B5 B6 B7 B8 Weeks Amlodipine (% initial) Initial100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 2 98.98 105.36100.82 97.67 100.22 98.62 98.70 99.05 4 97.06 104.08 99.24 95.90 97.9196.01 98.44 97.90 6 96.31 103.13 99.36 97.32 97.01 97.10 97.89 97.37 896.51 103.91 99.54 96.90 96.84 97.04 97.26 97.39 12 96.38 95.78 95.40 2692.69 95.34 94.49 Weeks USP Impurity A/EP Impurity D (wt % ofAmlodipine) Initial 0.05 0.04 0.03 0.03 0.03 0.03 0.00 0.04 2 0.17 0.100.08 0.07 0.07 0.05 0.04 0.05 4 0.22 0.12 0.10 0.08 0.07 0.09 0.07 0.086 0.28 0.15 0.11 0.10 0.08 0.12 0.09 0.09 8 0.32 0.16 0.13 0.11 0.120.12 0.11 0.11 12 0.16 0.14 0.13 26 0.24 0.23 0.22 Weeks Impurity RRT0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 2 0.07 0.08 0.09 0.09 0.08 0.09 0.13 0.12 4 0.19 0.19 0.19 0.180.19 0.22 0.28 0.25 6 0.28 0.28 0.28 0.26 0.26 0.33 0.38 0.36 8 0.340.33 0.34 0.34 0.33 0.40 0.47 0.44 12 0.51 0.55 0.55 26 0.60 0.63 0.63Weeks Total Impurities (wt % of Amlodipine) Initial 0.22 0.08 0.06 0.070.09 0.10 0.09 0.15 2 0.59 0.40 0.43 0.39 0.35 0.26 0.27 0.29 4 0.800.59 0.56 0.55 0.45 0.48 0.52 0.48 6 0.99 0.70 0.63 0.60 0.57 0.69 0.700.65 8 1.11 0.83 0.72 0.70 0.72 0.81 0.89 0.80 12 1.06 1.05 1.07 26 1.451.54 1.50

Example C. Effect of Hypromellose on the Formation of Degradants inAmlodipine Formulations

Formulations were prepared containing Amlodipine according to Table C-1.Each formulation was dispensed into screw-capped HDPE bottles and storedat both 5° C. and ambient temperature. Samples were removed periodicallyand analyzed using the HPLC method in Example A.

TABLE C-1 Composition (in mg/ml) of Amlodipine Formulations with VaryingHypromellose Content Formulation Component C1 C2 C3 C4 C5 C6 C7 C8Amlodipine besylate ^(a) 1.39 1.39 1.39 1.39 1.39 1.39 1.39 1.39Hypromellose K750 3.00 5.00 7.50 7.50 — — — — Citric acid, anhydrous0.55 0.55 0.55 0.55 0.55 0.55 0.55 0.55 Sodium benzoate 5.00 5.00 5.005.00 5.00 5.00 5.00 5.00 Sucralose 0.70 0.70 0.70 0.70 0.70 0.70 0.700.70 Simethicone 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 Silicon dioxide0.50 0.50 0.50 0.50 0.50 0.50 0.50 Artificial cherry — — — 0.50 — 0.50 —0.50 flavor Hypromellose K1500 — — — — 3.00 5.00 7.50 7.50 Water q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH 4.88 4.88 4.86 4.89 4.88 4.88 4.874.91 ^(a) = equivalent to 1 mg/ml Amlodipine

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at 5° C. are provided in Table C-2.

TABLE C-2 Assay and Primary Degradants Present in the FormulationsFormulation C1 C2 C3 C4 C5 C6 C7 C8 Weeks Amlodipine (% initial) Initial100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 4 100.00 97.1899.17 98.39 97.30 98.96 97.08 98.08 8 100.49 98.81 99.23 98.67 96.8898.32 96.76 98.17 12 99.72 99.17 100.27 99.57 95.76 98.49 97.42 98.95 2699.46 99.89 98.00 98.64 92.35 97.30 96.94 97.96 52 95.73 96.34 98.9199.67 96.59 100.29 97.44 96.27 78 98.78 98.10 98.74 99.14 99.39 97.9197.48 95.92 104 97.56 97.33 98.54 97.56 95.74 96.98 97.94 99.09 WeeksUSP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.01 0.03 0.010.16 0.02 0.10 0.02 0.11 4 0.01 0.02 0.03 0.17 0.02 0.11 0.03 0.10 80.03 0.03 0.03 0.21 0.02 0.11 0.04 0.12 12 0.03 0.04 0.04 0.21 0.03 0.100.04 0.11 26 0.02 0.05 0.05 0.26 0.03 0.11 0.06 0.15 52 0.06 0.04 0.070.35 0.06 0.14 0.07 0.20 78 0.06 0.11 0.11 0.41 0.07 0.18 0.10 0.24 1040.09 0.13 0.11 0.32 0.09 0.13 0.13 0.19 Weeks Impurity RRT 0.97 (wt % ofAmlodipine) Initial 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 4 0.00 0.010.01 0.00 0.00 0.00 0.01 0.00 8 0.01 0.02 0.02 0.02 0.01 0.02 0.02 0.0112 0.03 0.05 0.03 0.02 0.03 0.02 0.04 0.02 26 0.06 0.10 0.06 0.07 0.060.06 0.08 0.06 52 0.11 0.19 0.13 0.15 0.09 0.12 0.14 0.15 78 0.18 0.280.25 0.26 0.14 0.19 0.23 0.24 104 0.21 0.35 0.35 0.34 0.18 0.23 0.320.31 Weeks Total Impurities (wt % of Amlodipine) Initial 0.05 0.10 0.140.27 0.06 0.18 0.22 0.21 4 0.07 0.07 0.08 0.28 0.08 0.16 0.10 0.16 80.08 0.10 0.10 0.34 0.06 0.20 0.10 0.22 12 0.10 0.13 0.12 0.35 0.10 0.210.14 0.23 26 0.16 0.22 0.18 0.51 0.16 0.29 0.25 0.34 52 0.25 0.37 0.310.74 0.24 0.42 0.33 0.55 78 0.44 0.54 0.49 1.00 0.37 0.58 0.51 0.76 1040.46 0.73 0.61 1.02 0.44 0.65 0.63 0.80

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at ambient temperature are provided in Table C-3.

TABLE C-3 Assay and Primary Degradants Present in the FormulationsFormulation C1 C2 C3 C4 C5 C6 C7 C8 Weeks Amlodipine (% initial) Initial100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 2 100.27 98.62100.25 103.21 97.02 100.83 97.57 102.18 4 96.72 96.01 99.88 99.64 96.5797.86 97.00 98.33 6 100.45 97.10 — 100.18 96.32 98.48 — 98.24 8 99.8297.04 99.93 99.68 96.12 97.16 95.71 97.90 12 98.33 96.38 98.93 96.3195.40 97.05 96.84 96.80 26 96.35 92.69 96.55 94.46 92.50 94.29 94.3993.84 Weeks USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial0.01 0.03 0.01 0.16 0.02 0.10 0.02 0.11 2 0.03 0.05 0.08 0.27 0.03 0.120.07 0.16 4 0.05 0.09 0.10 0.35 0.04 0.14 0.09 0.20 6 0.06 0.12 — 0.470.05 0.19 — 0.24 8 0.09 0.12 0.13 0.56 0.06 0.21 0.12 0.32 12 0.08 0.160.17 0.73 0.08 0.29 0.16 0.40 26 0.16 0.24 0.26 1.30 0.16 0.50 0.25 0.70Weeks Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 2 0.05 0.09 0.10 0.08 0.05 0.07 0.09 0.08 4 0.130.22 0.20 0.19 0.12 0.17 0.17 0.19 6 0.20 0.33 — 0.30 0.17 0.24 — 0.29 80.24 0.40 0.40 0.41 0.21 0.30 0.33 0.37 12 0.32 0.51 0.58 0.58 0.26 0.380.49 0.50 26 0.38 0.60 0.89 0.91 0.30 0.47 0.69 0.69 Weeks TotalImpurities (wt % of Amlodipine) Initial 0.05 0.10 0.14 0.27 0.06 0.180.22 0.21 2 0.16 0.26 0.26 0.50 0.16 0.36 0.23 0.44 4 0.34 0.48 0.430.80 0.31 0.52 0.37 0.60 6 0.41 0.69 — 1.10 0.42 0.69 — 0.79 8 0.54 0.810.72 1.44 0.53 0.87 0.64 1.06 12 0.70 1.06 1.02 1.90 0.66 1.15 0.94 1.4026 1.02 1.45 1.64 3.40 1.00 1.97 1.44 2.45

Example D. Effect of Povidone on the Formation of Degradants inAmlodipine Formulations

Formulations were prepared containing Amlodipine according to Table D-1.Each formulation was dispensed into screw-capped HDPE bottles and storedat both 5° C. and ambient temperature. Samples were removed periodicallyand analyzed using the HPLC method in Example A.

TABLE D-1 Composition (in mg/ml) of Amlodipine Formulations with VaryingPovidone Content Formulation Component D1 D2 D3 D4 D5 D6 Amlodipine 1.391.39 1.39 1.39 1.39 1.39 besylate ^(a) Hypromellose — — — — — 3.00 K750Citric acid, 0.90 0.90 0.90 0.55 0.43 0.55 anhydrous Sodium benzoate7.50 7.50 7.50 5.00 3.00 5.00 Sucralose 0.70 0.70 0.70 0.70 0.70 0.70Simethicone — — — — — 0.15 Silicon dioxide 0.50 0.50 0.50 0.50 0.50 0.50K-90 Povidone 10.00 20.00 30.00 30.00 30.00 10.00 Water q.s. q.s. q.s.q.s. q.s. q.s. pH 4.87 4.89 4.92 4.96 4.83 4.91 ^(a) = equivalent to 1mg/ml Amlodipine

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at 5° C. are provided in Table D-2.

TABLE D-2 Assay and Primary Degradants Present in the FormulationsFormulation D1 D2 D3 D4 D5 D6 Weeks Amlodipine (% initial) Initial100.00 100.00 100.00 100.00 100.00 100.00 4 95.19 99.46 99.87 99.23101.99 97.83 8 96.51 98.13 99.21 96.18 102.95 99.57 12 96.40 96.19 97.8191.38 101.78 97.16 26 97.22 98.13 100.19 100.70 97.51 100.40 52 94.6696.70 99.27 89.30 93.84 99.65 78 96.81 98.79 99.53 98.55 89.66 100.84104 94.89 99.34 99.50 98.92 94.48 97.93 Weeks USP Impurity A/EP ImpurityD (wt % of Amlodipine) Initial 0.03 0.06 0.05 0.06 0.03 0.02 4 0.07 0.040.06 0.06 0.05 0.04 8 0.04 0.07 0.06 0.07 0.07 0.05 12 0.05 0.06 0.050.06 0.06 0.08 26 0.04 0.03 0.07 0.08 0.09 0.05 52 0.04 0.04 0.06 0.080.07 0.07 78 0.05 0.06 0.07 0.09 0.11 0.08 104 0.07 0.07 0.08 0.11 0.120.09 Weeks Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.000.00 0.00 0.00 4 0.00 0.00 0.00 0.00 0.00 0.00 8 0.00 0.00 0.00 0.000.00 0.01 12 0.00 0.00 0.00 0.00 0.00 0.01 26 0.00 0.00 0.01 0.01 0.020.05 52 0.01 0.01 0.02 0.02 0.03 0.10 78 0.01 0.02 0.03 0.04 0.05 0.14104 0.02 0.03 0.04 0.05 0.07 0.21 Weeks Total Impurities (wt % ofAmlodipine) Initial 0.09 0.11 0.10 0.09 0.07 0.07 4 0.11 0.08 0.10 0.120.10 0.08 8 0.10 0.14 0.10 0.12 0.12 0.10 12 0.18 0.17 0.21 0.12 0.130.14 26 0.11 0.16 0.18 0.16 0.19 0.16 52 0.17 0.15 0.24 0.16 0.20 0.2178 0.14 0.16 0.20 0.20 0.28 0.31 104 0.18 0.20 0.23 0.31 0.33 0.43

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at ambient temperature are provided in Table D-3.

TABLE D-3 Assay and Primary Degradants Present in the FormulationsFormulation D1 D2 D3 D4 D5 D6 Weeks Amlodipine (% initial) Initial100.00 100.00 100.00 100.00 100.00 100.00 2 94.21 97.15 98.15 91.0499.93 99.36 4 95.69 97.67 99.15 99.49 99.87 97.93 6 95.18 97.15 97.2097.49 101.11 98.11 8 94.74 96.16 96.17 98.99 98.59 99.38 12 91.38 95.0795.50 97.35 96.85 96.51 26 93.65 92.14 93.58 96.84 92.72 96.77 Weeks USPImpurity A/EP Impurity D (wt % of Amlodipine) Initial 0.03 0.06 0.050.06 0.03 0.02 2 0.06 0.07 0.08 0.12 0.10 0.10 4 0.07 0.08 0.08 0.120.13 0.10 6 0.08 0.11 0.10 0.16 — 0.12 8 0.08 0.10 0.12 0.17 0.17 0.1512 0.10 0.15 0.13 0.21 0.25 0.18 26 0.16 0.21 0.26 0.34 0.44 0.31 WeeksImpurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.00 0.000.00 2 0.00 0.01 0.02 0.01 0.01 0.05 4 0.02 0.03 0.05 0.04 0.05 0.13 60.03 0.04 0.06 0.06 — 0.20 8 0.04 0.06 0.08 0.08 0.08 0.25 12 0.04 0.070.09 0.09 0.10 0.32 26 0.05 0.10 0.13 0.13 0.14 0.41 Weeks TotalImpurities (wt % of Amlodipine) Initial 0.09 0.11 0.10 0.09 0.07 0.07 20.17 0.19 0.20 0.25 0.26 0.24 4 0.27 0.26 0.31 0.37 0.44 0.38 6 0.300.36 0.38 0.48 — 0.50 8 0.25 0.47 0.49 0.51 0.64 0.61 12 0.48 0.60 0.600.60 0.74 0.70 26 0.59 0.82 1.07 1.29 1.83 1.47

Example E. Formulations Containing 2-Naphthalene Sulfonate Salt Form ofAmlodipine

Formulations were prepared containing Amlodipine according to Table E-1.Each formulation was dispensed into screw-capped HDPE bottles and storedat both ambient temperature and 40° C. Samples were removed periodicallyand analyzed using the HPLC method in Example A.

TABLE E-1 Composition (in mg/ml) of Amlodipine Formulations FormulationComponent E1 E2 E3 Amlodipine besylate ^(a) 1.39 1.39 1.39 Sodium2-naphthalene 1.13 1.13 2.26 sulfonate Citric acid, anhydrous 0.31 0.310.31 Sodium citrate 0.42 0.42 0.42 Sodium benzoate 1.00 1.00 1.00Sucralose 0.70 0.70 0.70 Simethicone 0.15 0.15 0.15 Silicon dioxide 0.500.50 0.50 Artificial cherry — 0.50 — flavor Red 40 Al lake color — 0.015 — Hypromellose K750 5.00 5.00 5.00 Water q.s. q.s. q.s. pH 5.095.10 5.08 ^(a) = equivalent to 1 mg/ml Amlodipine

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at ambient temperature are provided in Table E-2.

TABLE E-2 Assay and Primary Degradants Present in the FormulationsFormulation Weeks E1 E2 E3 Amlodipine (% initial) Initial 100.00 100.00100.00 4 98.82 99.90 100.13 8 98.02 99.22 99.78 12 98.62 99.66 99.76 2697.56 98.86 99.99 52 98.80 100.17 99.51 78 98.46 100.15 100.21 104 98.36100.38 102.36 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial0.06 0.03 0.02 4 0.04 0.04 0.04 8 0.04 0.04 0.04 12 0.05 0.05 0.06 260.09 0.07 0.08 52 0.14 0.12 0.14 78 0.21 0.17 0.16 104 0.26 0.22 0.22Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 4 0.010.01 0.00 8 0.02 0.02 0.00 12 0.03 0.03 0.01 26 0.06 0.07 0.03 52 0.130.13 0.05 78 0.18 0.19 0.07 104 0.23 0.24 0.09 Total Impurities (wt % ofAmlodipine) Initial 0.31 0.51 0.45 4 0.10 0.10 0.08 8 0.10 0.09 0.13 120.12 0.12 0.12 26 0.23 0.26 0.17 52 0.42 0.36 0.36 78 0.50 0.48 0.31 1040.69 0.60 0.54

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at 40° C. are provided in Table E-3.

TABLE E-3 Assay and Primary Degradants Present in the FormulationsFormulation Weeks E1 E2 E3 Amlodipine (% initial) Initial 100.00 100.00100.00 2 98.23 98.65 98.59 4 98.20 98.67 99.41 8 95.28 97.08 97.82 1294.44 95.59 97.12 26 87.62 90.88 91.30 USP Impurity A/EP Impurity D (wt% of Amlodipine) Initial 0.06 0.03 0.02 2 0.13 0.12 0.12 4 0.20 0.190.19 8 0.42 0.33 0.44 12 0.67 0.47 0.87 26 1.95 1.06 5.18 Impurity RRT0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 2 0.11 0.12 0.05 4 0.190.20 0.09 8 0.32 0.33 0.15 12 0.38 0.39 0.20 26 0.41 0.41 0.20 TotalImpurities (wt % of Amlodipine) Initial 0.31 0.51 0.45 2 0.40 0.41 0.324 0.63 0.66 0.53 8 1.20 1.10 1.06 12 1.80 1.78 1.83 26 4.07 3.21 8.22

Example F. Stability of Amlodipine Formulations Prepared byTwo-Container, One-Container, and Pharmacy Compounding Processes

Formulation F6 was prepared by crushing 50 commercially available 5 mgamlodipine besylate tablets (Norvasc®, Pfizer Labs) with a mortar andpestle. A small amount of Ora-Blend (Paddock Laboratories, Inc.) wastriturated with the resulting powder, and then more Ora-Blend was addedgeometrically with mixing. The suspension was transferred to a graduatedcylinder and the mortar was rinsed with Ora-Blend. The rinse was addedto the cylinder then additional Ora-Blend was added to reach a finalvolume of 250 ml and the suspension was mixed. Formulations F1, F2, andF3 were prepared according to example 5B (one-container) andformulations F4 and F5 were prepared according to example 3A(two-container).

Each formulation was dispensed into screw-capped HDPE bottles and storedat both 5° C. and ambient temperature. Samples were removed periodicallyand analyzed using the HPLC method in Example A.

TABLE F-1 Composition (in mg/mL) of Amlodipine Formulations FormulationComponent F1 F2 F3 F4 F5 F6 Amlodipine besylate ^(a) 1.39 1.39 1.39 1.391.39 50 tablets Citric acid, anhydrous 0.31 0.31 0.31 0.31 0.31 — Sodiumcitrate, anhydrous 0.36 0.36 0.36 0.36 0.36 — Sodium benzoate 5.00 5.005.00 5.00 5.00 — Sucralose 0.70 0.70 0.70 0.70 0.70 — Simethicone 0.150.15 0.15 0.15 0.15 — Silicon dioxide 0.50 0.50 0.50 0.50 0.50 —Artificial cherry flavor 0.50 0.50 0.50 0.50 — — Polysorbate 80 0.501.00 2.00 1.00 1.00 — 0Hypromellose K1500 5.00 5.00 5.00 7.50 7.50 —Water q.s. q.s. q.s. q.s. q.s. — Ora-Blend ™ — — — — — q.s. to 250 ml pH5.31 5.33 5.35 5.35 5.36 4.64 ^(a) = equivalent to 1 mg/ml Amlodipine

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at 5° C. are provided in Table F-2.

TABLE F-2 Assay and Primary Degradants Present in the FormulationsFormulation F1 F2 F3 F4 F5 F6 Weeks Amlodipine (% initial) Initial100.00 100.00 100.00 100.00 100.00 100.0 2 99.23 100.74 99.17 — 101.85 —4 — — — 100.37 101.69 100.3 6 98.98 101.53 99.72 — 101.09 — 8 99.70100.86 99.06 101.12 101.40 97.2 12 98.98 100.49 98.91 100.35 101.12 26101.14 100.91 100.20 100.26 52 99.69 100.87 99.85 101.52 78 97.82 99.9498.94 101.72 104 99.74 99.90 98.19 Weeks USP Impurity A/EP Impurity D(wt % of Amlodipine) Initial 0.04 0.06 0.04 0.01 0.00 1.34 2 0.00 0.000.01 — 0.02 — 4 — — — 0.01 0.03 0.71 6 0.04 0.02 0.02 — 0.03 — 8 0.010.02 0.02 0.03 0.05 1.24 12 0.03 0.02 0.02 0.10 0.04 26 0.05 0.06 0.060.05 52 0.04 0.04 0.05 0.07 78 0.06 0.05 0.06 0.04 104 0.04 0.04 0.06Weeks Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.000.00 0.00 2 0.00 0.00 0.00 — 0.00 — 4 — — — 0.00 0.00 0.00 6 0.00 0.000.00 — 0.01 — 8 0.00 0.00 0.00 0.01 0.01 0.00 12 0.01 0.00 0.01 0.020.03 26 0.04 0.04 0.04 0.05 52 0.09 0.09 0.11 0.11 78 0.14 0.15 0.160.20 104 0.19 0.20 0.22 Weeks Total Impurities (wt % of Amlodipine)Initial 0.09 0.14 0.11 0.04 0.00 1.76 2 0.04 0.03 0.06 — 0.06 — 4 — — —0.04 0.08 1.00 6 0.07 0.05 0.06 — 0.09 — 8 0.05 0.06 0.07 0.06 0.08 1.5212 0.08 0.05 0.06 0.19 0.09 26 0.12 0.13 0.14 0.13 52 0.23 0.22 0.290.31 78 0.42 0.40 0.45 0.43 104 0.41 0.44 0.53

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at ambient temperature are provided in Table F-3.

TABLE F-3 Assay and Primary Degradants Present in the FormulationsFormulation F1 F2 F3 F4 F5 F6 Weeks Amlodipine (% initial) Initial100.00 100.00 100.00 100.00 100.00 100.0 2 100.65 100.52 99.57 101.16100.89 97.7 4 — — — 99.99 100.41 102.1 6 100.23 100.42 98.78 100.38100.47 94.3 8 99.16 100.28 98.99 102.38 100.68 90.6 12 99.71 99.46 98.52100.53 99.44 26 98.13 98.53 97.24 97.27 Weeks USP Impurity A/EP ImpurityD (wt % of Amlodipine) Initial 0.04 0.06 0.04 0.01 0.00 1.34 2 0.05 0.040.05 0.04 0.05 1.62 4 — — — 0.05 0.06 2.24 6 0.06 0.06 0.07 0.09 0.082.78 8 0.07 0.06 0.08 0.10 0.11 3.24 12 0.10 0.09 0.10 0.15 0.13 26 0.180.17 0.18 0.24 Weeks Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.000.00 0.00 0.00 0.00 0.00 2 0.03 0.03 0.04 0.03 0.04 0.03 4 — — — 0.060.10 0.05 6 0.12 0.13 0.13 0.11 0.13 0.09 8 0.17 0.17 0.17 0.17 0.180.11 12 0.23 0.23 0.24 0.28 0.30 26 0.36 0.35 0.36 0.49 Weeks TotalImpurities (wt % of Amlodipine) Initial 0.09 0.14 0.11 0.04 0.00 1.76 20.16 0.16 0.17 0.10 0.18 2.09 4 — — — 0.24 0.37 3.09 6 0.39 0.38 0.430.38 0.50 4.20 8 0.46 0.48 0.52 0.51 0.64 5.05 12 0.69 0.68 0.76 0.851.02 26 1.26 1.38 1.47 1.65

Example G. Effect of pH, Preservatives, and Hypromellose on Stability ofAmlodipine Benzoate Formulations at Accelerated Temperatures

Formulations were prepared containing Amlodipine according to Table G-1.Each formulation was dispensed into screw-capped HDPE bottles and storedat 60° C. Samples were removed periodically and analyzed using the HPLCmethod in Example A.

TABLE G-1 Composition (in mg/mL) of Amlodipine Formulations FormulationComponent G1 G2 G3 G4 G5 G6 G7 G8 Amlodipine besylate ^(a) 1.39 1.391.39 1.39 1.39 1.39 1.39 1.39 Citric acid, anhydrous 11.66 0.33 0.71 — —— 0.31 0.31 Sodium citrate, anhydrous — 0.35 — — — — 0.36 0.36Phosphoric acid — — — 0.96 0.67 0.39 — — Sodium benzoate 5.0 5.0 5.0 5.05.0 5.0 5.0 5.0 Sucralose 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 Methylparabensodium — — 1.72 1.72 1.72 1.72 — — Propylparaben sodium — — 0.17 0.170.17 0.17 — — Simethicone 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15Silicon dioxide 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Artificial cherry flavor0.5 0.5 0.5 0.5 0.5 0.5 — — Polysorbate 80 1.0 1.0 1.0 1.0 1.0 1.0 1.01.0 Hypromellose K1500 5.0 5.0 5.0 5.0 5.0 5.0 7.5 10.0 Water q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s pH 3.0 5.3 6.4 6.4 7.2 8.0 5.4 5.4 ^(a) =equivalent to 1 mg/ml Amlodipine

The results of the HPLC analysis for amlodipine and the main degradantsin the samples are provided in Table G-2.

TABLE G-2 Assay and Primary Degradants Present in the FormulationsFormulation G1 G2 G3 G4 G5 G6 G7 G8 Hours Amlodipine (% initial) 0100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 16 79.51 94.3793.87 92.75 91.50 85.26 — — 17 — — — — — — 93.42 96.47 36 — — — — — —90.28 — 40 66.39 91.31 91.68 92.04 85.87 75.43 — — 52 — — — — — — 87.3189.50 Hours USP Impurity A/EP Impurity D (wt % of Amlodipine) 0 0.200.03 0.03 0.03 0.06 0.03 0.03 0.01 16 2.39 0.16 0.14 0.24 0.24 0.21 — —17 — — — — — — 0.18 0.18 36 — — — — — — 0.29 — 40 4.24 0.29 0.21 0.350.34 0.35 — — 52 — — — — — — 0.58 0.50 Hours Impurity RRT 0.97 (wt % ofAmlodipine) 0 0.00 0.00 0.00 0.00 0.00 0.00 0.04 0.00 16 0.37 0.16 0.070.03 0.04 0.05 — — 17 — — — — — — 0.21 0.20 36 — — — — — — 0.44 — 400.52 0.30 0.15 0.08 0.08 0.13 — — 52 0.54 0.62 Hours Total Impurities(wt % of Amlodipine) 0 0.48 0.08 0.19 0.23 0.43 0.72 0.10 0.08 16 7.861.36 1.38 1.18 2.06 3.22 — — 17 — — — — — — 1.43 1.41 36 — — — — — —3.12 — 40 14.22 2.79 2.53 2.41 3.88 5.94 — — 52 — — — — — — 4.82 4.65

Example H. Effect of pH and Preservatives on Stability of AmlodipineNaphthalene Sulfonate Formulations at Accelerated Temperatures

Formulations were prepared containing Amlodipine according to Table H-1.Each formulation was dispensed into screw-capped HDPE bottles and storedat 60° C. Samples were removed periodically and analyzed using the HPLCmethod in Example A.

TABLE H-1 Composition (in mg/mL) of Amlodipine Formulations FormulationComponent H1 H2 H3 H4 H5 H6 Amlodipine besylate ^(a) 1.39 1.39 1.39 1.391.39 1.39 Citric acid, anhydrous 2.92 0.73 0.28 — — — Sodium citrate,anhydrous — — 0.41 — — — Phosphoric acid — — — 1.28 0.85 0.30 Dibasicsodium phosphate, — — — 0.31 — 0.18 heptahydrate Sodium benzoate 1.0 1.01.0 — — — Sodium 2-naphthalene 1.13 1.13 1.13 1.13 1.13 1.13 sulfonateSucralose 0.7 0.7 0.7 0.7 0.7 0.7 Methylparaben sodium — — — 1.72 1.721.72 Propylparaben sodium — — — 0.17 0.17 0.17 Simethicone 0.15 0.150.15 0.15 0.15 0.15 Silicon dioxide 0.5 0.5 0.5 0.5 0.5 0.5 Artificialcherry flavor 0.5 0.5 0.5 0.5 0.5 0.5 Polysorbate 80 1.0 1.0 1.0 1.0 1.01.0 Hypromellose K1500 5.0 5.0 5.0 5.0 5.0 5.0 Water q.s. q.s. q.s. q.s.q.s. q.s. pH 3.0 4.0 5.0 5.9 6.9 7.9

The results of the HPLC analysis for amlodipine and the main degradantsin the samples are provided in Table H-2.

TABLE H-2 Assay and Primary Degradants Present in the FormulationsFormulation H1 H2 H3 H4 H5 H6 Hours Amlodipine (% initial) 0 100.00100.00 100.00 100.00 100.00 100.00 16 90.01 96.31 97.94 99.10 99.7692.65 40 69.77 85.46 90.42 95.03 91.15 65.16 Hours USP Impurity A/EPImpurity D (wt % of Amlodipine) 0 0.07 0.03 0.04 0.08 0.06 0.23 16 1.440.33 0.14 0.37 0.42 0.40 40 4.98 2.65 1.01 0.88 0.75 1.14 Hours ImpurityRRT 0.97 (wt % of Amlodipine) 0 0.00 0.00 0.00 0.00 0.00 0.00 16 0.150.20 0.11 0.00 0.02 0.05 40 0.38 0.52 0.31 0.02 0.07 0.05 Hours TotalImpurities (wt % of Amlodipine) 0 0.13 0.09 0.25 1.09 2.92 5.57 16 3.441.17 0.81 1.76 3.04 13.64 40 10.82 5.76 3.39 3.21 6.92 35.53

Example I. Effect of Crystallization Time on the Formation of AmlodipineSalts a Formulation was Prepared in a Polyethylene Vessel with MagneticStirring

Purified water (33.5 kg) was added to the vessel and stirring wasinitiated. Polysorbate 80 (350 g) was added to the vessel along with a500 g aliquot of purified water used to rinse the polysorbate container.The solution was stirred for 10 minutes. Amlodipine Besylate (485.5 g)was then added to the vessel along with a 500 g aliquot of purifiedwater used to rinse the amlodipine container. The solution was stirredfor 5 minutes then 1750 g of sodium benzoate were added to thecontainer.

Samples were taken from the formulation every five minutes for an hour,filtered through 0.2 micron filters to isolate only the solubleamlodipine, and analyzed by HPLC for amlodipine content. The results ofthe HPLC analysis for the free amlodipine fraction are provided in FIG.1.

Example J. Stability of Formulations Using Avicel® RC-591 as theSuspending Agent

Formulations were prepared containing Amlodipine according to Table J-1.Each formulation was dispensed into screw-capped HDPE bottles and storedat both 5° C. and 25° C. Samples were removed periodically and analyzedusing the HPLC method in Example A.

TABLE J-1 Composition (in mg/ml) of Amlodipine Formulations FormulationComponent J1 J2 J3 Amlodipine 1.39 1.39 1.39 besylate ^(a) Citric acid,0.31 0.31 0.31 anhydrous Sodium citrate 0.36 0.36 0.36 Sodium benzoate5.00 5.00 5.00 Sucralose 0.70 0.70 0.70 Simethicone 0.15 0.15 0.15Artificial cherry 0.50 0.50 0.50 flavor Polysorbate 80 0.50 0.50 0.50Avicel ® RC-591 7.5  10.00  15.00  Water q.s. q.s. q.s. pH 5.36 5.335.34 ^(a) = equivalent to 1 mg/ml Amlodipine

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at 5° C. are provided in Table J-2.

TABLE J-2 Assay and Primary Degradants Present in the FormulationsFormulation Weeks J1 J2 J3 Amlodipine (% initial) Initial 100.00 100.00100.00 2 98.80 96.18 96.45 4 99.03 96.35 96.89 6 100.53 99.32 98.52 898.71 96.96 96.77 12 97.58 96.75 96.00 26 99.24 98.27 97.90 USP ImpurityA/EP Impurity D (wt % of Amlodipine) Initial 0.02 0.02 0.04 2 0.03 0.030.02 4 0.04 0.04 0.06 6 0.02 0.02 0.04 8 0.03 0.03 0.05 12 0.02 0.030.03 26 0.04 0.06 0.07 Impurity RRT 0.97 (wt % of Amlodipine) Initial0.00 0.00 0.00 2 0.00 0.00 0.00 4 0.00 0.00 0.00 6 0.00 0.00 0.00 8 0.000.00 0.00 12 0.00 0.00 0.00 26 0.01 0.01 0.01 Total Impurities (wt % ofAmlodipine) Initial 0.09 0.09 0.14 2 0.14 0.16 0.10 4 0.12 0.14 0.14 60.09 0.10 0.09 8 0.16 0.13 0.18 12 0.16 0.18 0.18 26 0.18 0.22 0.18

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at 25° C. are provided in Table J-3.

TABLE J-3 Assay and Primary Degradants Present in the FormulationsFormulation Weeks J1 J2 J3 Amlodipine (% initial) Initial 100.00 100.00100.00 2 99.27 97.16 96.52 4 98.94 97.73 96.89 6 99.61 98.81 98.20 897.34 96.91 95.85 12 95.57 95.48 93.25 26 95.39 93.67 92.65 USP ImpurityA/EP Impurity D (wt % of Amlodipine) Initial 0.02 0.02 0.04 2 0.05 0.040.06 4 0.06 0.04 0.06 6 0.08 0.05 0.06 8 0.05 0.06 0.08 12 0.06 0.070.09 26 0.09 0.09 0.13 Impurity RRT 0.97 (wt % of Amlodipine) Initial0.00 0.00 0.00 2 0.01 0.01 0.01 4 0.02 0.02 0.03 6 0.03 0.03 0.03 8 0.030.03 0.04 12 0.03 0.03 0.04 26 0.03 0.03 0.04 Total Impurities (wt % ofAmlodipine) Initial 0.09 0.09 0.14 2 0.20 0.27 0.28 4 0.38 0.39 0.42 60.52 0.55 0.59 8 0.69 0.73 0.83 12 0.96 1.11 1.15 26 1.64 1.37 1.98

Example K. Clinical Trial: Bioavailability Study of 5 mg Amlodipine OralSuspension Vs. Norvasc® 5 mg Tablets Under Fasted Conditions

The objective of this single dose open-label, randomized, two-period,two-treatment crossover study was to compare the relative oralbioavailability of a test formulation of 5 mL of amlodipine oralsuspension, 1 mg/mL (formulation F4), to an equivalent oral dose of thecommercially available comparator product, Norvasc® (amlodipinebesylate) 5 mg tablet, when administered under fasted conditions inhealthy adults.

Study design: Ten healthy adult subjects received a single 5 mL dose ofamlodipine oral suspension, 1 mg/mL, formulation F4 (Treatment A), inone period and a separate single dose of Norvasc® (amlodipine besylate)5 mg tablet (Treatment B) in another period. Each treatment wasadministered after an overnight fast of at least 10 hours, followed by a4-hour fast postdose.

During each period, blood samples were obtained prior to and followingeach dose at selected times through 168 hours postdose. Pharmacokineticparameters were calculated for each formulation using non-compartmentalmethods.

Statistical Methods: The concentration-time data were analyzed usingnoncompartmental methods in Phoenix™ WinNonlin® (Version 6.3, PharsightCorporation). Concentration-time data that were below the limit ofquantitation (BLQ) were treated as zero in the data summarization anddescriptive statistics. In the pharmacokinetic analysis, BLQconcentrations were treated as zero from time-zero up to the time atwhich the first quantifiable concentration was observed; embedded and/orterminal BLQ concentrations were treated as “missing”. Actual sampletimes were used for all pharmacokinetic and statistical analyses.Analysis of variance (ANOVA) and the Schuirmann's two one-sided t-testprocedures at the 5% significance level were applied to thelog-transformed pharmacokinetic exposure parameters, C_(max),AUC_(last), and AUC_(inf). The 90% confidence interval for the ratio ofthe geometric means (Test/Reference) was calculated. Bioequivalence wasdeclared if the lower and upper confidence intervals (CIs) of thelog-transformed parameters were within 80% to 125%.

Results: A total of 10 subjects participated in the study and 8 of thesesubjects completed both study periods. Based on the geometric meanratios of amlodipine AUCs (AUC_(last) and AUC_(inf)), thebioavailability of the amlodipine oral suspension (formulation F4)relative to the Norvasc® tablet was approximately 103% to 104%. Thegeometric mean ratio of amlodipine C_(max) was approximately 100%. The90% CI for comparing the maximum exposure to amlodipine, based on ln(C_(max)), was within the accepted 80% to 125% limits. The 90% CIs forcomparing total systemic exposure to amlodipine, based on ln(AUC_(last)) and ln (AUC_(inf)), was within the accepted 80% to 125%limits. Therefore, the 5 mL test formulation of amlodipine oralsuspension, 1 mg/mL, is bioequivalent to the reference product, Norvasc®(amlodipine besylate) tablet, 5 mg, under fasted conditions.

Example L. Characterization of Amlodipine Benzoate

A suspension was prepared by adding 0.50 g of NuSil Med-342 simethicone(30% simethicone) to 90 mL water in a glass beaker with stirring. Sodiumbenzoate (5.00 g) was added to the suspension and dissolved. Amlodipinebesylate (1.40 g) was added to 10 mL water, then the amlodipinesuspension was added to the benzoate suspension over 2-4 minutes. Theresulting suspension was mixed for 30 minutes at ambient temperature.

The solids were collected on filter paper and washed with ˜150 mL coldwater in 15 mL portions. The solid was dried under vacuum for 1 hour,then dried in a desiccator for 18 hours. A portion of the solids wereweighed and dissolved in water/HPLC diluent and the resulting solutionwas analyzed by a validated HPLC procedure for the presence ofamlodipine and benzoic acid. The resulting molar ratio of benzoicacid:amlodipine in the solid was calculated as 1.00:1.05 demonstratingthe formation of amlodipine benzoate.

Example M. Solubility of Amlodipine Besylate and Amlodipine Benzoate inthe Presence of Added Sodium Benzoate

Amlodipine benzoate was prepared by adding 1.39 g amlodipine besylate to100 ml purified water in a glass container. Five grams of sodiumbenzoate were then added and the solution was stirred for 30 minutes atambient temperature. The resulting suspension was vacuum filteredthrough #1 Whatman filter paper to collect the insoluble fraction. Thecollected solids were rinsed with ten separate 15 mL increments (150 mLtotal) of 1-5° C. degree water. The solids were dried on the vacuumfiltration apparatus for 1 hour then dried overnight in a desiccator.

Fifteen milliliter polypropylene centrifuge tubes were set up induplicate as shown in Table M-1. Amlodipine besylate or amlodipinebenzoate was added to each tube in amounts in excess of the anticipatedsolubility. Ten milliliter aliquots of water, or water with varyingamounts of sodium benzoate were added to each tube. The pH of each tubewas adjusted to 5.3 with the addition of citric acid. The tubes werecapped and mixed by inversion for 5 days to allow the suspensions toequilibrate. After the equilibration time, the tubes were opened andimmediately filtered through 0.45 micron nylon filters. The clearfiltrates were analyzed according to the method in Example A. Theresults of the HPLC analysis for the amounts of amlodipine in solutionare presented in FIG. 2.

TABLE M-1 Composition of Solubility Study Tubes Duplicate Tube SetComponent J1 J2 J3 J4 J5 J6 Amlodipine besylate (mg) 50 — — — — —Amlodipine benzoate (mg) — 50 50 50 50 50 Citric acid, anhydrous (mg)Amount as needed to achieve pH 5.3 Sodium benzoate (mg) 0 0 2 10 30 50Water (mL) 10 10 10 10 10 10 Measured pH 5.3 5.3 5.3 5.3 5.3 5.3

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method of treating hypertension in a subjectcomprising administering to the subject an oral liquid formulation,wherein the oral liquid formulation comprises: (i) amlodipine benzoatein an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml ofsodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/mlsimethicone; (vii) about 1.0 mg/ml of polysorbate 80; and (viii) water;wherein the pH of the formulation is between about 4 and about 6, andwherein the formulation is stable at about 5±5° C. for at least 12months; and wherein the stable oral liquid formulation has about 95% w/wor greater of the initial amlodipine amount and about 5% w/w or lesstotal impurities or related substances at the end of the given storageperiod.
 2. The method of claim 1, wherein the amlodipine benzoate isformed in situ.
 3. The method of claim 2, wherein the amlodipinebenzoate is formed by a reaction of a pharmaceutically acceptable saltof amlodipine that is more soluble in aqueous media than amlodipinebenzoate with a molar excess of sodium benzoate.
 4. The method of claim3, wherein the salt of amlodipine that is more soluble in aqueous mediathan amlodipine benzoate is selected from amlodipine besylate,amlodipine tosylate, amlodipine mesylate, amlodipine succinate,amlodipine salicylate, amlodipine maleate, amlodipine acetate, andamlodipine hydrochloride.
 5. The method of claim 2, wherein theamlodipine benzoate is formed by the reaction of amlodipine besylatewith a molar excess of sodium benzoate.
 6. The method of claim 1,wherein the formulation further comprises a flavoring agent.
 7. Themethod of claim 1, wherein the formulation further comprises asweetener.
 8. The method of claim 1, wherein the formulation is in theform of a suspension.
 9. The method of claim 1, wherein the pH isbetween about 5 and about
 6. 10. The method of claim 1, wherein theformulation is stable at about 5±5° C. for at least 24 months.
 11. Themethod of claim 1, wherein the hypertension is primary or secondaryhypertension.
 12. The method of claim 1, wherein the subject has bloodpressure values greater than or equal to 140/90 mm Hg.
 13. The method ofclaim 1, wherein the formulation is administered to the subject in afasted state or a fed state.
 14. The method of claim 1, wherein thesubject is an elderly.
 15. The method of claim 1, wherein the subject isan adult.
 16. The method of claim 1, wherein the subject is a child. 17.The method of claim 1, wherein the formulation is further administeredin combination with an agent selected from the group consisting ofdiuretics, beta blockers, alpha blockers, mixed alpha and beta blockers,calcium channel blockers, angiotensin II receptor antagonists, ACEinhibitors, aldosterone antagonists, and alpha-2 agonists.
 18. A methodof treating Coronary Artery Disease (CAD) in a subject comprisingadministering to the subject an oral liquid formulation, wherein theoral liquid formulation comprises: (i) amlodipine benzoate in an amountcorresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of acitrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodiumbenzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/mlof hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone;(vii) about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein thepH of the formulation is between about 4 and about 6, and wherein theformulation is stable at about 5±5° C. for at least 12 months; andwherein the stable oral liquid formulation has about 95% w/w or greaterof the initial amlodipine amount and about 5% w/w or less totalimpurities or related substances at the end of the given storage period.19. The method of claim 18, wherein the amlodipine benzoate is formed insitu.
 20. The method of claim 18, wherein the amlodipine benzoate isformed by a reaction of a pharmaceutically acceptable salt of amlodipinethat is more soluble in aqueous media than amlodipine benzoate with amolar excess of sodium benzoate.
 21. The method of claim 20, wherein thesalt of amlodipine that is more soluble in aqueous media than amlodipinebenzoate is selected from amlodipine besylate, amlodipine tosylate,amlodipine mesylate, amlodipine succinate, amlodipine salicylate,amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride.22. The method of claim 19, wherein the amlodipine benzoate is formed bythe reaction of amlodipine besylate with a molar excess of sodiumbenzoate.
 23. The method of claim 18, wherein the formulation furthercomprises a flavoring agent.
 24. The method of claim 18, wherein theformulation further comprises a sweetener.
 25. The method of claim 18,wherein the formulation is in the form of a suspension.
 26. The methodof claim 18, wherein the pH is between about 5 and about
 6. 27. Themethod of claim 18, wherein the formulation is stable at about 5±5° C.for at least 24 months.
 28. The method of claim 18, wherein the CAD ischronic stable angina, vasospastic angina, or angiographicallydocumented coronary artery disease.
 29. The method of claim 28, whereinthe angiographically documented coronary artery disease is in patientswithout heart failure or an ejection fraction <40%.
 30. The method ofclaim 18, wherein the formulation is further administered in combinationwith an additional anti-anginal agent.